Table of Contents
Overview
Definition of Signal Transduction
Signal transduction can be defined as the series of events through which a cell converts an extracellular signal into a specific intracellular response. This process is crucial in various physiological and developmental contexts, as it governs essential cellular functions such as growth, division, and the secretion of necessary molecules.[2.1] The mechanism of signal transduction involves several key steps, including the reception of a signal, transduction, and a subsequent cellular response. Initially, cells receive a signal when a ligand binds to the ligand-binding domain of a receptor protein. These ligands can be diverse, encompassing peptides, small chemicals, or proteins. A prominent example of a receptor protein involved in this process is the G protein-coupled receptor, which is commonly found in eukaryotic cells.[3.1] Signal transduction pathways serve as a critical link between the reception of a signal at the cell surface or within the cell and the eventual changes that occur inside the cell. They ensure that any chemical signal received by a receptor is appropriately translated into a functional response, thereby facilitating the necessary adjustments in cellular behavior.[4.1]Key Components of Signal Transduction Pathways
Signal transduction pathways are intricate networks that facilitate cellular communication in response to external stimuli. A fundamental aspect of these pathways is the role of receptors, which are classified into several types, including G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). GPCRs, the largest superfamily of cell surface receptors, are characterized by their seven-transmembrane (7TM) structure and are activated by a variety of extracellular signals such as hormones and neurotransmitters.[11.1] These receptors initiate signaling cascades by activating heterotrimeric G proteins, which subsequently regulate various cellular responses essential for processes like neurotransmission and immune function.[10.1] Receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) are both essential cell surface receptors that play significant roles in cell signaling processes. A key distinction between these two types of receptors is that RTKs have the ability to trigger multiple signal transduction pathways simultaneously upon the binding of a single ligand. In contrast, GPCRs typically engage in more linear signaling processes.[12.1] Understanding these differences is crucial for comprehending the mechanisms of cellular signaling and the specific pathways activated within the cell.[12.1] The specificity of signaling pathways is also influenced by the binding affinity of receptors for their ligands. For instance, the insulin receptor exhibits a high binding affinity specifically for insulin, which ensures precise signaling and cellular responses.[15.1] Moreover, the integration and amplification of signals from activated receptors lead to the expression of target genes in the nucleus, culminating in various biological responses.[17.1] Recent advances in our understanding of signal transduction pathways, also known as signaling cascades, have revealed their essential role as communication systems within cells. These pathways consist of a series of biochemical reactions initiated by external stimuli, transmitting information from the extracellular environment to the nucleus and leading to the activation or inhibition of specific genes.[6.1] In the context of cancer research, significant progress has been made in elucidating various key pathways, including Wnt/beta-catenin, Notch, and hedgehog; however, the primary focus has been on the Ras/Raf/MEK/ERK and PI3K/PTEN pathways.[18.1] Understanding these pathways is crucial for drug development, as researchers have discussed recent advances in targeting specific signal transduction pathways to improve the efficacy and safety of new pharmacological agents.[18.1]In this section:
History
Early Discoveries in Signal Transduction
The early discoveries in signal transduction laid the groundwork for our understanding of cellular communication and the mechanisms underlying physiological processes. One of the pivotal moments in this field occurred in 1920 when Professor Otto Loewi conducted an experiment that provided the first clear evidence for the chemical nature of nerve impulse transmission from nerve to muscle. This experiment, published in 1921, marked a significant advancement in neurophysiology and established a foundation for future research in signal transduction.[46.1] In the early 1950s, further breakthroughs were made by a research group led by John Eccles at the University of Otago, New Zealand. They convincingly demonstrated that synaptic transmission in the central nervous system is a chemical process, resolving a long-standing debate regarding the nature of synaptic signaling.[47.1] This discovery was crucial as it underscored the importance of chemical signaling in the nervous system, influencing subsequent studies on neurotransmitter function and receptor interactions. Additionally, advancements in the analysis of the sciatic nerve compound action potential during the early 20th century revealed changes in membrane ionic conductance that could be explained by gated and selective ion channels. This mechanistic understanding of ion channel behavior was instrumental in elucidating the processes involved in signal transduction.[48.1] The discovery of heterotrimeric GTP binding proteins (G proteins) as molecular switches further advanced the field by linking the activation of seven-membrane spanning receptors, known as G protein-coupled receptors (GPCRs), to second messenger-generating enzymes and ion channels. This paradigm shift provided a comprehensive framework for understanding cellular signal transduction pathways.[41.1]Evolution of Concepts in Cell Signaling
The evolution of concepts in cell signaling has been marked by significant milestones that have shaped our understanding of signal transduction. The early 20th century saw Paul Ehrlich introduce the "lock and key" theory, which emphasized the role of surface receptors in biological interactions, particularly with antigenic materials and drugs. This foundational idea posited that receptors function as sensory elements, interacting with specific ligands in a highly selective manner.[66.1] In the 1970s, the term "signal transduction" emerged in biological literature, with Martin Rodbell further developing the concept in 1980. He proposed that individual cells operate as cybernetic systems composed of three molecular components: discriminators (receptors), transducers, and amplifiers. This model illustrated how receptors receive external signals and transmit this information across the cell membrane.[39.1] The past few years have marked significant anniversaries in the field of signal transduction, highlighting key advancements in our understanding of cellular signaling mechanisms. Notably, this period has seen the identification of classic growth factors and morphogens, which play crucial roles in cellular communication and development. Additionally, the notion of protein modification through phosphorylation has been recognized as a fundamental aspect of signaling pathways. Furthermore, the characterization of protein interaction domains has contributed to a deeper understanding of the complex interactions that govern cellular signaling processes.[40.1] Recent technological advancements have further transformed the study of signal transduction. Techniques such as CRISPR and single-cell RNA sequencing have enabled researchers to observe and manipulate signaling pathways at unprecedented resolutions. For instance, CRISPR technology allows for precise gene editing, facilitating the investigation of genotype-phenotype interactions and their effects on signaling pathways.[56.1] Additionally, advancements in fluorescent biosensors have made it possible to measure signaling states at the single-cell level, providing insights into the dynamic nature of biological signaling networks.[55.1]In this section:
Mechanisms Of Signal Transduction
Types of Signaling Pathways
Signal transduction pathways are essential for mediating various biological functions in response to extracellular signals, including photons, ions, lipids, neurotransmitters, hormones, peptides, and odorants. Among these pathways, G protein-coupled receptors (GPCRs) constitute the largest superfamily of cell surface membrane receptors, encoded by approximately 1000 genes. GPCRs are characterized by their conserved seven-transmembrane (7TM) helices, which are connected by three intracellular and three extracellular loops.[85.1] These receptors are conformationally dynamic proteins that play a vital role in signal transduction, which is allosterically triggered by the distinct topography between the binding sites of extracellular stimuli and the subsequent intracellular signaling events.[85.1] Upon activation, GPCRs indirectly activate enzymes that generate intracellular second messengers, facilitating downstream signaling processes.[86.1] The mechanisms of signal transduction through GPCRs differ from those of other receptor types, such as receptor tyrosine kinases, highlighting the complexity of cellular responses to various stimuli.[85.1] The Wnt/β-catenin signaling pathway is integral to various cellular processes, including cell proliferation, fate determination, and migration, across multiple tissue types and organisms. In the nucleus, β-catenin acts as a co-activator for transcription factors of the TCF/LEF family, thereby modifying the expression of Wnt target genes and influencing key cellular behaviors depending on the specific cell type and state.[83.1] This pathway, along with others such as Erk and Notch, is dynamic and often dysregulated in cancer, underscoring its significance in both normal development and disease.[83.1] Furthermore, bioelectric circuits, which extend beyond neuronal signaling, play a crucial role in integrating information across various biological scales—from cells to whole organisms—facilitating morphogenesis and maintaining pattern homeostasis.[84.1] Understanding the interactions among these signaling pathways is essential for elucidating the mechanisms underlying embryogenesis and tissue regeneration, as well as for developing strategies to address developmental disorders and promote regeneration in cancer.[84.1] Signal transduction plays a crucial role in tissue remodeling and animal development. Specifically, the maintenance and regeneration of the epidermis is centrally controlled by a network regulated by the E2F transcription factor.[81.1] This network is integral to understanding how various signaling pathways interact during processes such as embryogenesis and tissue regeneration. For instance, in the context of somatic embryogenesis, competent cells within explants can respond to inductive signals, primarily plant growth regulators, leading to the formation of somatic embryos from somatic cells.[82.1] This interaction highlights the importance of signaling pathways in developmental processes and their implications for understanding developmental disorders. In the realm of oncology, understanding specific signaling pathways is crucial for the development of targeted therapies that can significantly improve clinical outcomes. Two key pathways, the PI3K/AKT/mTOR signal transduction pathway and the Ras/MAPK pathway, are frequently activated or mutated in various cancers, underscoring their relevance in tumorigenesis.[88.1] A deeper comprehension of how these signaling pathways influence the malignant behavior of cancer cells may pave the way for novel targeted therapies.[89.1] Furthermore, molecular alterations in cancer genes and associated signaling pathways are increasingly utilized to inform new treatments within the framework of precision medicine. Small molecule inhibitors and monoclonal antibodies that target relevant cancer-related proteins have proven instrumental in the successful treatment of certain blood malignancies and solid tumors.[92.1]Role of Receptors and Ligands
Receptors and ligands are fundamental components of signal transduction pathways, which are sequences of events that link the receipt of a cell signal to a specific cellular response.[79.1] During this process, a signal may consist of various components, including primary messengers such as chemical signals, electrical pulses, or physical stimuli.[77.1] Receptor proteins, located on or within target cells, interact with these signaling molecules, known as ligands, to initiate a cascade of chemical changes inside the cell.[79.1] This interaction leads to a conformational change in the receptor, which is crucial for triggering physiological responses.[107.1] The efficiency of these signal transduction pathways is significantly influenced by the specificity and affinity of receptor-ligand interactions, which are a major class of protein-protein interactions essential for various biological processes, including metabolism and neurotransmission.[107.1] The interaction between receptors and ligands is characterized by specificity and affinity, which are influenced by the structural characteristics of the receptor proteins. These proteins consist of various domains, and the unique combinations of structural motifs in their extracellular regions determine their specificity for particular ligands.[108.1] The binding of ligands to receptors often involves multiple contact points, enhancing the efficiency of the signal transduction process.[108.1] The binding affinity between a receptor and its ligand is quantitatively described by the binding constant (Kb). A higher Kb value is associated with a more negative standard free energy of binding, which indicates that the kinetic parameters, including the association rate constant (kon) and the dissociation rate constant (koff), along with their ratio (Kb), are critical in determining the thermodynamic properties of the receptor-ligand complex. This relationship highlights the stability of the complex and the binding affinity between the protein and ligand.[110.1] Understanding these kinetic parameters is essential, as they directly influence the specificity and efficiency of signal transduction pathways within the cell.[110.1] In the field of personalized medicine, biomarkers are recognized as essential tools. They play a significant role in the early detection, prognosis, and diagnosis of diseases, as well as in predicting treatment responses. This capability allows healthcare providers to select appropriate individuals for treatment, ensuring that the right medication is administered to the right patient.[115.1] The ongoing development of biomarkers continues to enhance the effectiveness of personalized medicine approaches, ultimately contributing to improved therapeutic outcomes.[115.1]In this section:
Recent Advancements
Innovations in Research and Technology
Recent advancements in research and technology have significantly enhanced our understanding of signal transduction pathways. One of the most notable developments is the ability to study signal transduction at the single-cell level, facilitated by technological advances that allow for the observation of cellular responses, computational modeling of signaling pathways, and experimental manipulation of cells. This capability is crucial for comprehending the dynamic nature of biological signaling networks, as it enables researchers to measure the signaling state of specific molecules with high precision using fluorescent biosensors.[131.1] Recent years have witnessed significant advances in our understanding of the complexity of signal transduction pathways, as well as the isolation of specific inhibitors targeting key components within these pathways.[117.1] The application of computational techniques to model biological systems, particularly signaling pathways, has increased, driven by the vast amounts of experimental data generated from high-throughput technologies.[128.1] Among these computational methods, Petri net approaches have emerged as effective tools for exploring the dynamics of signal transduction networks without the necessity for extensive kinetic parameters.[125.1] These models have been instrumental in evaluating and validating various aspects of specific signaling pathways, such as the epidermal growth factor (EGF) signaling pathway, where they have provided insights into the kinetic behavior of key members of the MAPK cascade over time.[127.1] This integration of computational modeling with experimental data has the potential to enhance our understanding of complex biological processes, although challenges remain in obtaining sufficient and high-quality kinetic data.[128.1] Recent advancements in technology have significantly enhanced our understanding of the complexity of signal transduction pathways. High-throughput screening, single-cell RNA sequencing, and advanced imaging techniques have enabled researchers to study the dynamic nature of these pathways in real time, revealing previously unknown cellular behaviors.[133.1] Among the most notable innovations in optical imaging for signal transduction is the introduction of the green fluorescent protein (GFP) from the jellyfish Aequorea. This protein allows for the genetic encoding of strong visible fluorescence, facilitating the visualization of signaling events in live cells.[134.1] Over the past few years, both random and semirational mutagenesis have produced GFP variants with new colors, further expanding the toolkit available for studying cellular processes.[134.1] Moreover, interdisciplinary research programs that combine computational modeling with experimental analysis are being developed to validate models against experimental data. This approach emphasizes the importance of comparing model predictions with real-world observations, thereby enhancing the reliability of computational models in predicting cellular responses.[144.1] Overall, these innovations in research and technology are paving the way for a more comprehensive understanding of signal transduction mechanisms, with implications for biomedical and pharmaceutical applications.Applications in Medicine and Therapeutics
Recent advancements in signal transduction have revolutionized the development of targeted therapies and regenerative medicine. Targeted therapeutic drugs, especially small-molecule inhibitors, have become pivotal in cancer treatment due to their enhanced efficacy and safety over traditional chemotherapy. Since the FDA's approval of the first tyrosine kinase inhibitor, imatinib, in 2001, numerous small-molecule targeted drugs have been developed, although challenges like low response rates and drug resistance remain.[118.1] Understanding key signaling pathways has been instrumental in creating therapeutic strategies for tissue repair and regeneration. Research highlights the potential of manipulating macrophage function by targeting specific signaling pathways and transcription factors. The TLR9 signaling pathway, for instance, promotes macrophage M2 polarization, aiding tissue regeneration.[135.1] Macrophage plasticity is crucial in coordinating inflammation, angiogenesis, and matrix remodeling, essential for restoring tissue homeostasis. By leveraging this plasticity, novel therapeutic strategies targeting macrophage polarization can be developed for various diseases.[138.1] Additionally, the TGF-β signaling pathway influences cellular behaviors such as proliferation and apoptosis, which are critical for therapeutic outcomes.[123.1] In regenerative medicine, discoveries in signal transduction pathways have led to innovative therapeutic approaches. For example, the activation of the CXCR4/RhoA signaling pathway enhances adipose tissue regeneration by attracting stem cells, suggesting the potential of stem cell-derived migrasomes as therapeutic targets.[137.1] Furthermore, the Hippo signaling pathway's downstream effectors, YAP and TAZ, are being explored as therapeutic targets for cancer treatment, with research focusing on pharmacologic manipulation of pathways interacting with Hippo signaling.[136.1] The development of signal transduction inhibitors, particularly kinase inhibitors, has been crucial in cancer therapy. These inhibitors block chemical signals that mediate cellular responses, providing a targeted treatment approach.[139.1] As research continues to unravel the complexities of signal transduction pathways, integrating these findings into clinical practice remains a challenge, necessitating effective stakeholder collaboration to translate research into improved patient outcomes.[121.1]In this section:
Interactions And Networks
Crosstalk Between Signaling Pathways
Crosstalk between signaling pathways is a critical aspect of cellular communication, allowing cells to integrate various signals and respond appropriately to their environment. Receptor Tyrosine Kinases (RTKs) are integral components of these signaling networks, mediating cell-to-cell communication and influencing fundamental cellular processes such as growth, differentiation, metabolism, and survival.[171.1] Upon ligand binding, RTKs undergo dimerization, which activates their intracellular tyrosine kinase domains, leading to autophosphorylation and the initiation of downstream signaling cascades.[170.1] One of the primary pathways activated by RTKs is the phosphoinositide 3-kinase (PI3K) pathway, which plays a crucial role in regulating cell proliferation, differentiation, and survival.[168.1] The activation of PI3K leads to the phosphorylation of downstream effectors, including Akt, which promotes anabolic processes and cellular growth.[165.1] Additionally, RTKs also interact with the mitogen-activated protein kinase (MAPK) pathway, further illustrating the complexity and versatility of signaling networks.[178.1] The interplay between these pathways is essential for maintaining cellular homeostasis. For instance, the PI3K and MAPK pathways can modulate each other's activity, allowing cells to fine-tune their responses to external stimuli.[178.1] Disruptions in this crosstalk can lead to pathological conditions, including cancer, where aberrant signaling can result in uncontrolled cell growth and proliferation.[168.1] Furthermore, the concept of immunometabolism highlights the interaction between metabolic pathways and immune responses, suggesting that alterations in signaling pathways can have widespread implications for various diseases, including obesity and type 2 diabetes.[164.1]Formation of Signaling Networks
Signal transduction pathways are essential for cellular communication, linking the reception of signals at the cell surface or within the cell to subsequent intracellular changes. These pathways ensure that chemical signals received by receptors are effectively translated into functional responses, thereby playing a critical role in maintaining homeostasis and regulating physiological processes.[152.1] The complexity of these pathways is underscored by the interactions among various signaling molecules, including receptor tyrosine kinases (RTKs), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways, which illustrate the intricate networks involved in signal transduction.[153.1] The formation of signaling networks is facilitated by the interactions of proteins and small molecules that transmit information from the cell surface to the nucleus, ultimately leading to transcriptional changes.[155.1] These networks are characterized by their ability to integrate multiple signals and respond to environmental stimuli, which is crucial for cellular adaptation and function. For instance, the activation of cytoplasmic receptors, such as NOD-like receptors (NLRs), can initiate signaling cascades that influence cell proliferation, growth, and metabolism.[154.1] Bioinformatics tools serve as essential instruments for elucidating the complexities of signaling networks, functioning similarly to digital microscopes that allow scientists to identify proteins, analyze interactions, and visualize intricate biological networks.[158.1] These tools facilitate the identification and visualization of protein-protein interactions, which are crucial for understanding the dynamics of signal transduction. For instance, STRING not only incorporates physical protein-protein interactions but also leverages additional evidence such as coexpression and literature mining.[157.1] BioGRID further enhances this understanding by distinguishing between low- and high-throughput analyses, while MINT catalogs the number of experiments supporting each interaction and the type of evidence available.[157.1] The applications of bioinformatics-driven proteomics are significant, contributing to advancements in drug discovery, disease diagnostics, and personalized medicine.[158.1] Computational models of signal transduction networks significantly enhance our understanding of cellular responses by utilizing protein-interaction maps generated from large-scale two-hybrid screens and expression profiles from DNA microarrays. These models are designed to generate static representations of the networks, which are determined entirely by integrating protein-protein interaction data with microarray expression data.[174.1] Furthermore, they can disentangle the highly intertwined regulatory networks and identify system-wide behaviors, potentially leading to the discovery of new therapeutic targets.[175.1] Overall, the formation of signaling networks is a complex process that relies on the integration of various molecular components through advanced computational approaches.Implications In Disease
Role in Cancer and Metabolic Disorders
Dysregulation of the Wnt signaling pathway is a critical factor in the development and progression of various cancers, including colorectal cancer (CRC). This pathway plays essential roles in cellular processes such as proliferation, differentiation, and survival, and its aberration is linked to numerous malignancies.[205.1] In CRC specifically, alterations in the Wnt signaling pathway are universally observed, with over 90% of cases exhibiting mutations in key regulatory genes such as APC and CTNNB1.[206.1] The aberrant Wnt/β-catenin signaling pathway not only facilitates cancer stem cell renewal but also influences cell proliferation and differentiation, thereby playing crucial roles in tumorigenesis and response to therapy.[207.1] As a result, therapeutic strategies targeting the Wnt signaling pathways are currently under active development, with several drugs and inhibitors designed specifically for cancers that are driven by these pathways.[204.1] Furthermore, while hyperactivation of Wnt signaling is common across many cancer types, the specific genetic alterations can vary significantly, indicating potential cancer-specific mechanisms for Wnt-driven diseases.[209.1] The role of signal transduction in the development of metabolic disorders and cancer is significant, particularly due to the dysfunction of G protein-regulated pathways, which have been linked to various endocrine diseases.[195.1] This dysfunction highlights the importance of understanding these pathways in the context of disease mechanisms. Furthermore, dysregulated cell signaling is a driving factor in numerous diseases, including cancer and metabolic disorders, underscoring the urgent need for targeted therapies.[199.1] Developing drugs that specifically modulate these signaling pathways shows great promise for treatment, as evidenced by the efficacy of receptor tyrosine kinase inhibitors in cancers characterized by aberrant signaling.[199.1] This approach not only addresses the immediate therapeutic needs but also paves the way for personalized medicine, which tailors treatments based on individual genetic and molecular profiles.[199.1] In addition to cancer and metabolic disorders, the interplay between signal transduction and hormone action is crucial in endocrine physiology. Research has shown that secreted Wnt inhibitors, such as sclerostin, are implicated in the progression of metabolic diseases and endocrine dysfunction.[197.1] This highlights the multifaceted role of signal transduction pathways in both cancer and metabolic disorders, emphasizing the potential for therapeutic interventions that target these critical signaling mechanisms.Signal Transduction in Neurodegenerative Diseases
Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by a myriad of complex aetiologies.[226.1] Understanding the common biochemical molecular pathologies among these diseases provides an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration.[226.1] These interrelated mechanisms highlight the importance of investigating the disruptions in signaling pathways that may contribute to the pathophysiology of NDDs.[226.1] Alterations in key signaling pathways, including those involving Akt and Erk, have been implicated in the pathogenesis of multiple neurodegenerative disorders. These pathways are essential regulators of cell survival, motility, transcription, metabolism, and cell cycle progression.[202.1] For instance, disruptions in Akt and Erk-mediated signaling contribute significantly to the development of conditions such as Alzheimer's and Parkinson's diseases.[202.1] Furthermore, the aggregation of abnormal proteins, a hallmark of major neurodegenerative disorders, activates various signal transduction pathways, exacerbating neuronal injury and dysfunction.[203.1] Specific examples of disrupted signaling pathways include the glutaminase/glutamate/NMDA receptor signaling cascade and the mitogen-activated protein kinase (MAPK) pathways, which are crucial in the pathophysiology of neurodegenerative diseases. Abnormalities in these pathways can lead to the activation of inflammatory cytokines, such as TNF-α and IL-6, which further contribute to neuronal damage.[222.1] Additionally, mitochondrial dysfunction and oxidative stress are central to the pathogenesis of these diseases, highlighting the intricate relationship between cellular signaling and neurodegeneration.[225.1] Recent studies have also identified non-canonical signaling pathways arising from mitochondrial dysfunction that may serve as novel therapeutic targets for neurodegenerative diseases.[223.1] The exploration of these pathways, alongside traditional signaling mechanisms, could pave the way for innovative treatment strategies aimed at mitigating the effects of neurodegeneration and improving patient outcomes.[225.1]In this section:
Future Directions
Emerging Research Areas
Recent advancements in peptide drug development have significantly influenced the field of signal transduction. Over the past decade, the integration of new production, modification, and analytic technologies has facilitated the development of therapeutic peptides, which are produced and modified through both chemical and biological methods. These innovations have enabled researchers to overcome inherent drawbacks associated with peptides, thereby advancing the field further.[228.1] One notable area of research is the exploration of specific signal transduction pathways, particularly the Ras/Raf/MEK/ERK and PI3K/PTEN pathways, which are critical in cancer biology. Recent studies have highlighted the importance of these pathways, while also acknowledging advancements in understanding other key pathways such as Wnt/beta-catenin, Notch, and hedgehog.[229.1] Moreover, the ability to study signal transduction at the single-cell level has been enhanced by recent technological advances. These include improved methods for observing cellular responses, computational modeling of signaling pathways, and experimental manipulation of cells. Such advancements allow for a more nuanced understanding of dynamic biological signaling networks, as they enable researchers to measure the activation levels of specific molecules within signal transduction pathways at single-cell resolution.[234.1] The study of cell-to-cell heterogeneity in signal transduction responses is crucial for understanding how signaling pathways mediate cell communication and coordinate essential cellular functions such as proliferation, differentiation, and energy metabolism.[232.1] Single-cell analyses serve as a valuable tool in this context, as they can reveal insights that are often obscured in population experiments. However, the inherent variability among cells can complicate the interpretation of signaling functions unless the role of this heterogeneity is also elucidated.[231.1] Recent advancements in mass-spectrometry, microchip technologies, and reiterative staining-based techniques have significantly enhanced the evaluation of cellular heterogeneity, allowing for high-throughput analyses with increased multiplexity and sensitivity.[233.1] These innovations enable deep profiling of single-cell proteomics, which is essential for a comprehensive understanding of cell signaling functions. The integration of novel peptide delivery systems with emerging technologies, particularly nanotechnology and synthetic biology, is set to significantly enhance the efficacy of signal transduction-based therapies. The advent of nanotechnology-based drug delivery systems has opened new frontiers in the treatment of various diseases, including chronic respiratory conditions, by facilitating receptor activation and signal transduction processes.[241.1] Over the past two decades, nanotechnology has revolutionized medicine and biomedical engineering, making nanobased peptide delivery systems crucial for the targeted and efficient delivery of therapeutic peptides.[242.1] Furthermore, the combination of synthetic biology with advancements in nanotechnology has ushered in a new era for developing targeted drug delivery systems, allowing for the creation of engineered nanomaterials with tailored morphologies and functions.[243.1] This transformative impact of engineered nanomaterials is essential for improving therapeutic outcomes in signal transduction therapies.Potential for Drug Development
Recent advancements in peptide drug discovery have significantly enhanced our understanding of signal transduction pathways, which has important implications for developing targeted therapies. The progress in peptide drug development over the last decade has been facilitated by innovations in production, modification, and analytical technologies, allowing for the creation of peptides that can effectively interact with various signaling mechanisms.[235.1] For instance, peptides derived from the C-terminal region of Gα subunits have been shown to selectively inhibit hormonal signal transduction by acting as antagonists at G protein-coupled receptors (GPCRs).[236.1] This specificity in targeting signal transduction pathways underscores the potential of peptides as therapeutic agents. Peptide-based therapies, particularly glucagon-like peptide-1 receptor (GLP-1R) agonists, have gained prominence in the treatment of various metabolic diseases, including diabetes and cardiovascular disorders. GLP-1R, a core member of the G protein-coupled receptor (GPCR) family, is widely present on the surfaces of various cells in the human body and plays a crucial role in regulating blood glucose levels and lipid metabolism by specifically binding to the key hormone GLP-1.[228.1] These receptor agonists mimic the action of endogenous GLP-1, activating GLP-1R to enhance insulin secretion, inhibit glucagon release, delay gastric emptying, and reduce food intake through central appetite suppression.[228.1] The therapeutic potential of GLP-1R agonists is underscored by their ability to reshape treatment approaches for multiple diseases, including diabetes, cardiovascular disorders, and neurodegenerative diseases.[228.1] Recent clinical trials, including the SURPASS phase III trials, have demonstrated that GLP-1R agonists outperform single receptor agonists, further solidifying their role in managing metabolic syndrome.[228.1] Additionally, promising candidates such as retaglutide are being explored for their efficacy in treating type 2 diabetes mellitus (T2DM), fatty liver disease, and obesity by targeting multiple receptors, including GLP-1R, glucagon receptor (GCGR), and gastric inhibitory polypeptide receptor (GIPR).[228.1] The advancements in peptide drug research highlight the significant impact of these therapies on improving treatment strategies for metabolic disorders.[228.1] Moreover, the versatility of peptide-based technologies is further illustrated by their application in diagnostic settings, such as the use of peptide radiopharmaceuticals for detecting neuroendocrine tumors.[238.1] This adaptability not only emphasizes the therapeutic potential of peptides but also their role in advancing precision medicine. Despite these advancements, challenges remain in the modification and delivery of peptide therapeutics. Enhancements in peptide stability and activity are crucial for improving their drug-like properties.[259.1] Strategies for subcellular targeting of peptides have been explored to ensure that therapeutic agents are delivered to specific organelles, thereby maximizing their efficacy in modulating signal transduction pathways.[260.1] By overcoming these obstacles, the future of peptide-based drug development holds promise for more effective treatments targeting complex signaling networks involved in various diseases.References
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[40] Signalling change: signal transduction through the decades — The past few years have marked significant anniversaries in signal transduction, including the identification of classic growth factors and morphogens, the notion of protein modification through phosphorylation and the characterization of protein interaction domains. Here, six researchers reflect on …
[41] Cell Signaling - Cell Press — The discovery that heterotrimeric GTP binding proteins (G proteins) act as molecular switches, linking the activation of seven-membrane spanning receptors (also known as hepathelical or serpentine receptors) to second messenger-generating enzymes and ion channels, provided a working paradigm for cellular signal transduction. In these pathways
[46] One hundred years from Otto Loewi experiment, a dream that ... — The paper reported an ingenious, yet straightforward experiment made by Professor Otto Loewi in 1920 and published in 1921, which constitutes the first clear-cut proof for the chemical nature of transmission of the nerve impulse from nerve to muscle. The approach to this experiment was, however, tortuous and long. ... History, 20th Century
[47] John Eccles (1903-97) and the experiment that proved chemical synaptic ... — One of the most important experiments in neurophysiology in the twentieth century took place in the physiology laboratories at the University of Otago, New Zealand, in August 1951. The group of researchers led by John Eccles convincingly established that synaptic transmission in the central nervous system was a chemical process. This work was the culmination of a long debate between advocates
[48] A brief history of nerve action potentials after 1600 — After the analysis of the sciatic nerve compound action potential in the early 20th century, the mechanistic denouement came when electronic amplifiers and intracellular recording from single giant fibers revealed membrane ionic conductance changes that could be explained in terms of gated and selective ion channels.
[55] Signal transduction at the single-cell level: Approaches to study the ... — Recent technological advances to observe cellular response, computationally model signaling pathways, and experimentally manipulate cells now enables studying signal transduction at the single-cell level. The ability to fully comprehend signal transduction at the single-cell level requires advancements in how we observe cells, model cellular behavior, and manipulate biological systems. In the following review we will discuss the specific methods and developments used to observe, model, and manipulate biological systems to study dynamic signal transduction at the single-cell level. Measuring the signaling state, or the level of activation of a specific molecule in a signal transduction pathway, at the single-cell level based on fluorescent biosensors as described above requires quantifying the fluorescent levels at single-cell resolution. Signal transduction studies at the single-cell level provide information about the dynamic nature of biological signaling networks.
[56] Illumina's high-throughput single-cell CRISPR prep makes gene editing a ... — Now, Illumina scientists have developed a high-throughput method that allows researchers to interrogate the whole transcriptome of individual cells following gene perturbation by CRISPR-Cas9. “Illumina’s method is particularly important because it allows researchers to efficiently investigate the interactions between genotype and phenotype following CRISPR-Cas9-mediated gene expression perturbation, enabling them to understand specific pathways at an unprecedented scale,” says Kristina Fontanez, senior director of product development at Illumina. Now, with Illumina’s scalable CRISPR screening methods, “you [have] the statistical power to evaluate the impact of knocking out every gene, one at a time, on a cell-by-cell basis,” explains Robert Meltzer, associate principal scientist at Illumina and a fellow cofounder of Fluent BioSciences. PIPs helped solve the issue of preparing high-throughput samples for single-cell analysis, and the Illumina NovaSeq X efficiently analyzes the CRISPR-Cas9-perturbed transcriptomes of those cells.
[66] PDF — The concept of receptors as sensory elements in biology has a long history. Early in this century Paul Ehrlich realized the importance of surface receptors and postulated a "lock and key" theory to explain their interactions with antigenic materials and drugs. Today, it is understood tl~at receptors are proteins with the patterns of design and malleability of structure required for discriminat
[77] Signal Transduction: Definition, Pathways, Examples - Biology Dictionary — The different routes which signal transduction takes to carry a signal are known as signal transduction pathways. Signal Transduction Pathway. During signal transduction, a signal may have many components. There is the primary messenger, which may be a chemical signal, electrical pulse, or even physical stimulation. Then, the receptor protein
[79] Introduction to Signal Transduction | AP® Biology Revision — AP Environmental Science Introduction to Signal Transduction (College Board AP® Biology) : Study Guide A signal transduction pathway is the sequence of events that links receipt of a cell signal with a cellular response The signal is provided by a chemical signaling molecule known as a ligand; ligands bind to receptors on or in specific target cells Transduction is the series of chemical changes that occurs inside a cell which result in an eventual cellular response The signalling cascade that occurs during transduction eventually brings about a specific response inside the cell Ligands can bind to extracellular receptors, initiating a cascade of chemical reactions inside the cell that result in altered gene expression
[81] Mechanisms of Cellular Signal Transduction - PMC - PubMed Central (PMC) — Signal transduction also underlies tissue remodeling and animal development. For instance, the maintenance and regeneration of the epidermis is centrally controlled by the E2F transcription factor regulated network. ... On pages 87-95, Ivanova et. al provide an update on the functions and mechanisms of action for the various components of the
[82] Transduction of Signals during Somatic Embryogenesis - MDPI — Somatic embryogenesis (SE) is an in vitro biological process in which bipolar structures (somatic embryos) can be induced to form from somatic cells and regenerate into whole plants. Acquisition of the embryogenic potential in culture is initiated when some competent cells within the explants respond to inductive signals (mostly plant growth regulators, PRGs), and de-differentiate into
[83] Signalling dynamics in embryonic development - PMC — Here, we focus on Erk, Wnt and Notch signalling pathways, which are dynamic in several tissue types and organisms, including the periodic segmentation of vertebrate embryos, and are often dysregulated in cancer. In the nucleus, β-catenin functions as a co-activator for transcription factors of the TCF/LEF family and modifies the expression of Wnt target genes [126–128], thereby leading to changes in key cellular processes including cell proliferation, cell fate determination and migration depending on cell type and cell state. While the Wnt/β-catenin pathway and the molecular interactions of signalling components are extensively studied, only a few studies investigate the dynamics of Wnt signalling and how cells receive, process, and interpret different features of extracellular ligands, such as molecular identity, concentration, and combinations with other ligands to control specific cellular behaviour.
[84] Bioelectric signaling: Reprogrammable circuits underlying embryogenesis ... — Michael Levin provides a perspective on how bioelectric circuits—beyond neurons—integrate information across cell, tissue, organ, and whole-body scales to enable morphogenesis and pattern homeostasis. A roadmap for exploiting bioelectric communication to treat developmental disorders, promote regeneration, reprogram cancer, and engineer living things is presented.
[85] G protein-coupled receptors (GPCRs): advances in structures, mechanisms ... — G protein-coupled receptors (GPCRs) are the largest superfamily of cell surface membrane receptors and are encoded by approximately 1000 genes, sharing conserved seven-transmembrane (7TM) helices connected by three intra- and three extra-cellular loops.1,2,3 GPCRs are conformationally dynamic proteins that mediate vital biological functions of signal transduction triggered by various extracellular signals such as photons, ions, lipids, neurotransmitters, hormones, peptides, and odorants.4,5,6,7,8 Due to the distinct topography between the binding sites of extracellular stimuli and the subsequent signaling events at the intracellular site (approximately 40 Å), GPCR signal transduction is allosteric.9,10,11,12,13 Advances in protein engineering, X-ray crystallography, and cryo-electron microscopy (cryo-EM), coupled with innovative technologies such as X-ray free electron lasers (XFELs) and nuclear magnetic resonance (NMR) spectroscopy, have revolutionized our understanding of GPCR structures and dynamics. In addition, molecular dynamics (MD) simulations offer a comprehensive, time-resolved view of complete protein structures, capturing intermediate states along the transition pathway.46,47,48 Advances in the structural biology of GPCRs have revealed key information on ligand-receptor interactions, conformational changes, and signaling complexes, opening the opportunity for exploration of receptor activation, orthosteric/allosteric modulation, biased signaling, and dimerization.
[86] Intracellular Signal Transduction by G protein coupled receptor 'GPCR ... — Signaling by G protein coupled receptor. The way the signals are transduce is different in various intracellular pathways that transduce signals downstream from activated cell-surface receptors. G protein coupled receptors indirectly activate enzymes that generate intracellular second messengers as mentioned above. They combine through GTP
[88] Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial ... — In this review, we will focus on a few signaling pathways and on selected types of cancer for which targeted therapies have significantly contributed to improve clinical outcomes. Two pathways in particular, the PI3K/AKT/mTOR signal transduction pathway and the Ras/MAPK pathway, are frequently activated or mutated in cancer.
[89] Signaling pathways in brain tumors and therapeutic interventions - Nature — Importantly, a better understanding of targeting signaling pathways that influences malignant behavior of brain tumor cells might open the way for the development of novel targeted therapies.
[92] Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial ... — Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors
[107] Receptor-Ligand Interactions - Bruker — Receptor-ligand interactions are a major class of protein-protein interactions and play an important role in many biological processes such as metabolism, neurotransmission and cellular signal transduction pathways. When a ligand binds to a protein, it undergoes a conformational change which in turn leads to a physiological response.
[108] Cell signalling: 2.2 Receptor specificity - OpenLearn — Proteins can be thought of as consisting of various domains, and the different combinations of structural motifs in the extracellular regions of receptors will confer the specificity of a receptor for its ligand. Ligand binding may involve multiple sites of contact between the ligand and different domains of the receptor.
[110] Insights into Protein-Ligand Interactions: Mechanisms, Models, and ... — Equation (4) makes it apparent that the higher the binding constant Kb, the more negative the standard free energy of binding, indicating that the kinetic parameters (kon and koff and their ratio Kb) determine the thermodynamic properties of the complex, i.e., the stability of the complex and the binding affinity between the protein and ligand. 210.Cossins B.P., Foucher S., Edge C.M., Essex J.W. Protein-ligand binding affinity by nonequilibrium free energy methods. 216.Wang W., Wang J., Kollman P.A. What determines the van der Waals coefficient beta in the LIE (linear interaction energy) method to estimate binding free energies using molecular dynamics simulations?
[115] Role of Biomarkers in Personalized Medicine | SpringerLink — Biomarkers are a key tool in medicine, especially in the domain of personalized medicine. They are valuable for the early detection, prognosis, and diagnosis of disease as well as for the prediction of treatment response. They enable us to select appropriate individuals for treatment with personalized medicine and provide the right medication to the right patient. At present, the development
[117] Advances in Targeting Signal Transduction Pathways - PMC — Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore
[118] Small molecules in targeted cancer therapy: advances ... - Nature — Advertisement View all journals Search Log in Explore content About the journal Publish with us Sign up for alerts RSS feed nature signal transduction and targeted therapy review articles article Small molecules in targeted cancer therapy: advances, challenges, and future perspectives Download PDF Download PDF Review Article Open access Published: 31 May 2021 Small molecules in targeted cancer therapy: advances, challenges, and future perspectives Lei Zhong1,2 na1, Yueshan Li ORCID: orcid.org/0000-0003-2343-12521 na1, Liang Xiong ORCID: orcid.org/0000-0003-1174-56091 na1, Wenjing Wang1 na1, Ming Wu1, Ting Yuan2, Wei Yang1, Chenyu Tian1, Zhuang Miao1, Tianqi Wang1 & … Shengyong Yang1 Show authorsSignal Transduction and Targeted Therapy volume 6, Article number: 201 (2021) Cite this article 157k Accesses 15 Altmetric Metrics details Subjects Drug development Drug discovery Abstract Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.
[121] Identifying barriers and facilitators of translating research evidence ... — The study concluded that recognising barriers and facilitators could help set key priorities that aid in translating and integrating research evidence into practice. Effective stakeholder collaboration and co-operation should improve the translation of research findings into clinical practice.
[123] Signaling pathways activated and regulated by stem cell-derived exosome ... — The effects of TGF-β signal transduction pathway are cellular context-dependent, on cell type, growth phase, differentiation status, and epigenetic state . The TGF-β signaling could induce cytostasis in some cells, but also determine cellular behaviors such as proliferation, apoptosis, autophagy, senescence, and dormancy in others [ 71 ].
[125] Computational modeling of signal transduction networks without kinetic ... — Computational modeling of signal transduction networks without kinetic parameters: Petri net approaches Am J Physiol Cell Physiol. 2023 May 1;324(5):C1126-C1140. doi: 10.1152/ajpcell.00487.2022. Epub 2023 Mar 6. Authors ... for example, logical models or Petri net models. These techniques make it possible to explore system's dynamics without
[127] Modeling and simulation in signal transduction pathways: a systems ... — Using this computational model, several aspects of the EGF signaling pathway were evaluated and validated. Fig. 4 shows the explanatory 3D graphs demonstrating how the EGF and overexpression of receptor mediates the EGFR signal transduction pathway with respect to time. The kinetic behavior of key members of the MAPK cascade at different EGF
[128] Computational modeling of signal transduction networks without kinetic ... — More and more computational techniques have been applied to model biological systems, especially signaling pathways in medical systems. Due to the large number of experimental data driven by high-throughput technologies, new computational concepts have been developed. Nevertheless, often the necessary kinetic data cannot be determined in sufficient number and quality because of experimental
[131] Signal transduction at the single-cell level: Approaches to study the ... — Recent technological advances to observe cellular response, computationally model signaling pathways, and experimentally manipulate cells now enables studying signal transduction at the single-cell level. The ability to fully comprehend signal transduction at the single-cell level requires advancements in how we observe cells, model cellular behavior, and manipulate biological systems. In the following review we will discuss the specific methods and developments used to observe, model, and manipulate biological systems to study dynamic signal transduction at the single-cell level. Measuring the signaling state, or the level of activation of a specific molecule in a signal transduction pathway, at the single-cell level based on fluorescent biosensors as described above requires quantifying the fluorescent levels at single-cell resolution. Signal transduction studies at the single-cell level provide information about the dynamic nature of biological signaling networks.
[133] Signal Transduction Pathway | Zoologytalks | 2025 — 4. Emerging Research and Innovations in Signal Transduction. Recent advancements in technology have enabled deeper insights into the complexity of signal transduction. High-throughput screening, single-cell RNA sequencing, and advanced imaging techniques have allowed researchers to study the dynamic nature of signaling pathways in real time. a.
[134] Recent advances in technology for measuring and manipulating cell ... — In the last few years, perhaps the biggest advance in technology for the optical imaging of signal transduction pathways has been the introduction of the green fluorescent protein (GFP) from the jellyfish Aequorea, which enables genetic encoding of strong visible fluorescence.Over the last several years, both random and semirational mutagenesis have produced GFP variants with new colors
[135] Macrophage plasticity: signaling pathways, tissue repair, and regeneration — Manipulating macrophage function by targeting specific signaling pathways and transcription factors has emerged as a promising therapeutic strategy for promoting tissue repair and regeneration. The TLR9 signaling pathway has been found to encourage macrophage M2 polarization in various models. 505 Activation of the TLR9 pathway, such as with
[136] Targeting the Hippo Signaling Pathway for Tissue Regeneration and ... — The downstream effectors of the Hippo signaling pathway, YAP and TAZ, are promising therapeutic targets for the treatment of cancer. To inhibit YAP and TAZ, most research is focused on the pharmacologic manipulation of signaling pathways that cross-talk with the Hippo pathway, as well as the development of compounds that disrupt the
[137] Migrasomes, critical players in intercellular communication — By activating the CXCR4/RhoA signaling pathway, CXCL12 can attract stem cells and enhance adipose tissue regeneration. These findings suggest that utilizing ASC-derived migrasomes as novel therapeutic targets for ASC-mediated tissue regeneration holds great potential and may have broader applications in regenerative medicine.
[138] Macrophage plasticity: signaling pathways, tissue repair, and ... — Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases
[139] Other Signal Transduction Inhibitors - Callaix — Signal Transduction Inhibitors are medicines that block chemical signals from cell to cell. These signals are part of often-complex biochemical pathways that produce a cellular response. Most of the signal transduction inhibitors in clinical use are kinase inhibitors. Other types find uses in cancer therapy, too.
[144] (PDF) Validation of models with experimental data and analysis of ... — This study explores the methods and techniques for validating models against experimental data, emphasizing the importance of comparing model predictions with real-world observations to assess
[152] Signal Transduction Basics: AP® Biology Review - Albert — Overview of signal transduction pathways These pathways form a critical link between the reception of the signal at the cell surface (or inside the cell) and the eventual changes that happen inside the cell. They ensure that any chemical signal received by a receptor is appropriately translated into a functional response. Components of a Signal
[153] Signal Transduction Pathways in Cellular Communication — Signal Transduction Pathways in Cellular Communication - BiologyInsights Cells rely on signal transduction pathways to communicate and respond to their environment, playing a role in maintaining homeostasis and regulating physiological processes. RTKs also interact with other signaling molecules, such as the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, illustrating their complexity and versatility. Ion channel receptors facilitate the rapid passage of ions across cell membranes, directly influencing cellular excitability and signal transduction. These small molecules are generated or released within the cell in response to receptor activation and serve to distribute signals to various intracellular targets. Protein phosphorylation is a fundamental mechanism in cellular signaling, influencing a wide range of biological activities by modifying proteins’ functional states.
[154] Review Article: An Overview of Cellular Signal Transduction Pathway — The main subclass of cytoplasmic receptors is the NOD-like receptors (NLRs).Recently identified NLRs found in the cell’s cytoplasm and react with ligands by a Leucine-Rich Repeat (LRR) do its response as that of TLRs. The components asNOD2react with receptor-interacting protein kinase 2 (RIPK2)which stimulate nuclear factor kabba B (NF-κB) signaling, whereas others like NACHT, LRR and PYD domains-containing protein 3 (NALP3or cryopyrin) react with inflammatory caspases and start processing of specificcytokinesasinterleukin-1β [49-51]. These mechanisms for controlling cell proliferation, growth, metabolism and other processes .The stimulation of many marked pathways through a receptor of singling plasma membrane as well as stimulation of many second messengers through theses effectors may activate a development of signaling transduction, activate diverse, pleiotropic, responses according to the type of the cell .
[155] Automated Modelling of Signal Transduction Networks — Background: Intracellular signal transduction is achieved by networks of proteins and small molecules that transmit information from the cell surface to the nucleus, where they ultimately effect transcriptional changes. Understanding the mechanisms cells use to accomplish this important process requires a detailed molecular description of the networks involved. Results: We have developed a
[157] Building Protein-Protein Interaction Networks with Proteomics and ... — For example, STRING not only uses physical protein-protein interaction but also utilizes other evidence such as coexpression or mining of publications. BioGRID distinguishes between low- and high-throughput analyses, and MINT itemizes the number of experiments showing the interaction as well as the evidence for interaction ( e.g. direct
[158] Bioinformatics-Driven Proteomics - ChemTalk — Bioinformatics tools act like digital microscopes, enabling scientists to identify proteins, analyze interactions, and visualize complex biological networks. Bioinformatics-driven proteomics has significant practical applications, such as accelerating drug discovery, improving disease diagnostics, and advancing personalized medicine.
[164] Metabolic regulation of the immune system in health and diseases ... — More than a decade ago, the concept of immunometabolism was proposed to summarize the interaction between metabolism and immunity (Fig. 1).3 In the beginning, researchers noted only inflammatory responses in metabolic disorders, including obesity, insulin resistance, and type 2 diabetes mellitus (T2DM), to define immunometabolism.3,4,5,6 After summarizing the differences of metabolic pathways in activated and quiescent immune cells, the definition of immunometabolism has been greatly expanded.7,8 Soon afterward, metabolic pathways of T cells have been discussed as a promising entry point for cancer immunotherapy.9 Then, benefiting from accessibility of measuring cellular metabolism of immune cells, immunometabolism has been introduced in studies on many other diseases, becoming an emerging and booming field.
[165] A nexus for cellular homeostasis: the interplay between metabolic and ... — Extracellular signals activate two major signaling cascades controlled by the activation of PI3K and Ras. PI3K and Ras regulate Akt and ERK, which in turn induce changes in intermediate metabolism to promote anabolic processes. In addition to protein synthesis, mTORC1 has been recently implicated in the regulation of other major metabolic pathways of the cell, including lipid and nucleic acid synthesis, glycolysis, glutaminolysis, TCA cycle and oxidative phosphorylation, further supporting the idea of mTORC1 as a master regulator of metabolism . Thus, AMPK, SIRT1 and the TTT-RUVBL complex fine-tune signaling transduction in accordance to the energetic state of the cell, regulating the balance between anabolic and catabolic processes, thereby maintaining cellular homeostasis (Fig.2). In this report authors show for the first time that activation of oncogenic K-Ras induces a glucose-associated metabolic rewiring towards anabolic processes, fueling pancreatic tumor cell growth and proliferation.
[168] Receptor tyrosine kinases in PI3K signaling: The therapeutic targets in ... — The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway (PI3K/AKT), a critical signal transduction system correlated with essential cellular functions, such as cell survival, proliferation and differentiation, contributes to tumorigenesis in different types of cancer .Receptor tyrosine kinases (RTKs) are the common upstream activators for many important signal pathways including PI3K/AKT
[170] Receptor Tyrosine Kinases Explained: Definition, Examples, Practice ... — Receptor Tyrosine Kinases (RTKs) are integral membrane proteins with an intracellular Tyrosine Kinase domain that phosphorylates tyrosine residues on target proteins. RTKs typically exist as monomers but dimerize upon ligand binding, leading to autophosphorylation and full activation. This activation allows RTKs to phosphorylate target proteins, initiating a cascade of cellular responses
[171] Receptor tyrosine kinases: mechanisms of activation and signaling — Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that mediate cell-to-cell communication. These single-pass transmembrane receptors, which bind polypeptide ligands — mainly growth factors — play key roles in processes such as cellular growth, differentiation, metabolism and motility.
[174] Automated modelling of signal transduction networks | BMC ... — We have developed a computational approach for generating static models of signal transduction networks which utilizes protein-interaction maps generated from large-scale two-hybrid screens and expression profiles from DNA microarrays. Networks are determined entirely by integrating protein-protein interaction data with microarray expression
[175] Computational modeling of signal transduction networks without kinetic ... — Computational models can disentangle the highly intertwined regulatory network and identify the system-wide behavior. The study of computational models may lead to a better understanding of the biological function and therefore, may identify new therapeutic targets. ... Predicting essential components of signal transduction networks: a dynamic
[178] Signal Transduction Pathways in Cellular Communication — Signal Transduction Pathways in Cellular Communication - BiologyInsights Cells rely on signal transduction pathways to communicate and respond to their environment, playing a role in maintaining homeostasis and regulating physiological processes. RTKs also interact with other signaling molecules, such as the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, illustrating their complexity and versatility. Ion channel receptors facilitate the rapid passage of ions across cell membranes, directly influencing cellular excitability and signal transduction. These small molecules are generated or released within the cell in response to receptor activation and serve to distribute signals to various intracellular targets. Protein phosphorylation is a fundamental mechanism in cellular signaling, influencing a wide range of biological activities by modifying proteins’ functional states.
[195] Signal transduction and human disease : Free Download, Borrow, and ... — Signal transduction and human disease ... This book uniquely relates the broad impact of signal transduction research on the understanding and treatment of human disease. ... Dysfunction of G protein-regulated pathways and endocrine diseases / William F. Simonds -- Bacterial regulation of the cytoskeleton / Jeremy W. Peck, Dora C. Stylianou
[197] Metabolism and Endocrine Disorders: What Wnt Wrong? - PMC — Wnt Signaling Pathway and Endocrine Systems ... Sclerostin is a secreted Wnt inhibitor that has emerged in the progression of metabolic disease and endocrine dysfunction. ... Stannek P, et al. Casein Kinase 1 Gamma Couples Wnt Receptor Activation to Cytoplasmic Signal Transduction. Nature (2005) 438(7069):867-72. doi: 10.1038/nature04170
[199] How Dysregulated Cell Signaling Causes Disease - News-Medical.net — As dysregulated cell signaling drives numerous diseases, there is an urgent need for targeted therapies.14 Developing drugs that modulate specific signaling pathways holds immense promise for treating conditions like cancer, neurodegenerative diseases, and autoimmune disorders.1 For example, inhibitors of receptor tyrosine kinases (RTKs) have shown efficacy in cancers driven by aberrant RTK signaling.15 Nonetheless, the future of medicine lies in personalized approaches, tailoring treatments based on an individual's genetic and molecular profile.14 This could involve identifying specific mutations driving disease and selecting drugs that precisely target those dysregulated pathways.14 Retrieved on December 03, 2024 from https://www.news-medical.net/health/How-Dysregulated-Cell-Signaling-Causes-Disease.aspx. <https://www.news-medical.net/health/How-Dysregulated-Cell-Signaling-Causes-Disease.aspx>. https://www.news-medical.net/health/How-Dysregulated-Cell-Signaling-Causes-Disease.aspx. News-Medical, viewed 03 December 2024, https://www.news-medical.net/health/How-Dysregulated-Cell-Signaling-Causes-Disease.aspx.
[202] The Role of PI3K/Akt and ERK in Neurodegenerative Disorders - Springer — Disruption of Akt and Erk-mediated signal transduction significantly contributes in the pathogenesis of various neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's diseases, Huntington's disease, and many others. These regulatory proteins serve as the regulator of cell survival, motility, transcription, metabolism, and progression of the cell cycle. Therefore
[203] Basic mechanisms of neurodegeneration: a critical update — Neurodegenerative diseases are characterized by progressive dysfunction of specific populations of neurons, determining clinical presentation. ... 'neuroinflammatory' processes and (secondary) disruptions of neuronal Golgi apparatus and axonal transport. ... Accumulation of aggregation-prone proteins activates signal transduction pathways
[204] Therapeutic targets in the Wnt signaling pathway: Treating cancer with ... — This review systematically examines the Wnt signaling pathways in cancer, summarizing their molecular mechanisms and modes of action. ... Therapeutic strategies targeting Wnt signaling pathways are under active development, with several drugs and inhibitors designed specifically for cancers targeting this pathway (Table 2 and Fig. 4).
[205] Emerging therapeutic strategies for Wnt-dependent colon cancer ... — The Wnt signaling pathway plays a critical role in various cellular processes, including proliferation, differentiation, and cell survival (Teo and Kahn, 2010; Tejeda-Muñoz and Mei, 2024).It is fundamental in embryonic development and tissue homeostasis in adults (Sharma and Pruitt, 2020).Dysregulation of Wnt signaling has been linked to numerous diseases, particularly cancer (Sharma and
[206] Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy — Colorectal cancer. The Wnt signaling pathway alterations are universally observed in CRC tissues, with more than 90% of CRC cases harboring mutations in genes such as APC, CTNNB1, RNF42, AXIN1, or RSPO ... Therapeutic strategies targeting Wnt/β-catenin signaling pathway. Currently, many Wnt/β-catenin signaling pathway inhibitors have become
[207] Targeting the Wnt/β-catenin signaling pathway in cancer - PMC — The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic
[209] WNT as a Driver and Dependency in Cancer — The WNT signaling pathway is a critical regulator of development and adult tissue homeostasis and becomes dysregulated in many cancer types. Although hyperactivation of WNT signaling is common, the type and frequency of genetic WNT pathway alterations can vary dramatically between different cancers, highlighting possible cancer-specific mechanisms for WNT-driven disease.
[222] Disruptions in cellular communication: Molecular interplay between ... — This manuscript reviews the crucial roles of cellular signalling pathways in the pathophysiology of these conditions, focusing primarily on glutaminase/glutamate/NMDA receptor signalling, alongside the mitogen-activated protein kinase (MAPK) pathways—ERK1/2, C-JNK, and P38 MAPK. Abnormalities in signalling pathways can lead to numerous neurological conditions like Multiple Sclerosis, PD, and AD (Tanaka et al., 2020) via the activation of inflammatory cytokines such as TNF-α and IL-6. The c-JNK signalling pathway activation enhances c-jun expression and phosphorylation (Yarza et al., 2016). The involvement of the glutaminase/glutamate/NMDA receptor (NMDA-R)/ERK1/2/C-JNK/p38 MAPK cascade is pathophysiologically significant in numerous disorders of the nervous system: Alzheimer's, Parkinson's, Huntington's, schizophrenia (Parkin et al., 2018) and other known mental illnesses and brain trauma (Raffaele et al., 2023, Rosina et al., 2019, Bohush et al., 2018, Deutsch and Luyo, 2022).
[223] Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation ... — The exploration of these non-canonical pathways arising from mitochondrial dysfunction and contributing to neurodegeneration may unveil novel targets for the development of therapeutics. Here, we discuss these pathways in the setting of two common neurodegenerative diseases (AD and PD) and DS, the most frequent progeroid syndrome.
[225] Oxidative stress and mitochondrial impairment: Key drivers in ... — The intricate relationship between mitochondrial dysfunction and oxidative stress plays a central role in the pathogenesis of neurodegenerative diseases. Understanding and targeting these pathways could pave the way for new therapeutic strategies, offering hope for improved outcomes for patients suffering from these debilitating conditions.
[226] Biochemical and Molecular Pathways in Neurodegenerative Diseases: An ... — Abstract Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated
[228] Therapeutic peptides: current applications and future directions — Peptide drug development has made great progress in the last decade thanks to new production, modification, and analytic technologies. Peptides have been produced and modified using both chemical and biological methods, together with novel design and delivery strategies, which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field.
[229] Advances in Targeting Signal Transduction Pathways - PMC — In this review, we have discussed some of the recent advances in targeting certain signal transduction pathways. Although there have been many advances in our understanding of other key pathways involved in cancer such as Wnt/beta-catenin [ 190 ], Notch [ 191 ] and hedgehog [ 192 ], we have primarily focused on the Ras/Raf/MEK/ERK and PI3K/PTEN
[231] Single-cell Analysis of G-protein Signal Transduction - PMC — Single-cell analyses are something of a mixed blessing in this respect as they can provide valuable information that is lost in population experiments, but the natural heterogeneity of a signal may hinder the understanding of its function unless the role of the heterogeneity can also be determined.
[232] Profiling Cell Signaling Networks at Single-cell Resolution — Cell-to-Cell Heterogeneity in the Signal Transduction Response. Signaling pathways mediate cell communication and coordinate cellular functions such as proliferation, differentiation, and energy metabolism (1 -4).They are often regulated by phosphorylation events mediated by kinases and phosphatases that result in the controlled activity of downstream effector molecules.
[233] Deep Profiling of Cellular Heterogeneity by Emerging Single-Cell ... — Recent advances in mass-spectrometry, microchip, and reiterative staining-based techniques for single-cell proteomics have enabled the evaluation of cellular heterogeneity with high throughput, increased multiplexity, and improved sensitivity. State-of-the-art multicolor flow cytometry technique can detect ~10 different types of proteins in single cells with a high-throughput manner but still limited by the low multiplexing capacity because of spectral overlap of fluorophore-labeled antibodies, and it cannot capture secreted proteins that are essential to understand cell signaling functions . To enable deep profiling of cellular heterogeneity, new methods for single-cell protein analysis with high detection sensitivity and multiplexing capability have recently developed, which herein be categorized as mass spectrometry-based, microchip-based, and reiterative staining methods.
[234] Signal transduction at the single-cell level: Approaches to study the ... — Recent technological advances to observe cellular response, computationally model signaling pathways, and experimentally manipulate cells now enables studying signal transduction at the single-cell level. The ability to fully comprehend signal transduction at the single-cell level requires advancements in how we observe cells, model cellular behavior, and manipulate biological systems. In the following review we will discuss the specific methods and developments used to observe, model, and manipulate biological systems to study dynamic signal transduction at the single-cell level. Measuring the signaling state, or the level of activation of a specific molecule in a signal transduction pathway, at the single-cell level based on fluorescent biosensors as described above requires quantifying the fluorescent levels at single-cell resolution. Signal transduction studies at the single-cell level provide information about the dynamic nature of biological signaling networks.
[235] Therapeutic peptides: current applications and future directions — Advertisement View all journals Search Log in Explore content About the journal Publish with us Sign up for alerts RSS feed nature signal transduction and targeted therapy review articles article Therapeutic peptides: current applications and future directions Download PDF Download PDF Review Article Open access Published: 14 February 2022 Therapeutic peptides: current applications and future directions Lei Wang1 na1, Nanxi Wang2 na1, Wenping Zhang1 na1, Xurui Cheng1 na1, Zhibin Yan1, Gang Shao3, Xi Wang3, Rui Wang4,5 & … Caiyun Fu ORCID: orcid.org/0000-0003-4090-885X1 Show authorsSignal Transduction and Targeted Therapy volume 7, Article number: 48 (2022) Cite this article 326k Accesses 132 Altmetric Metrics details Subjects Drug development Drug screening Abstract Peptide drug development has made great progress in the last decade thanks to new production, modification, and analytic technologies. Peptides have been produced and modified using both chemical and biological methods, together with novel design and delivery strategies, which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field. This review summarizes the efforts and achievements in peptide drug discovery, production, and modification, and their current applications. We also discuss the value and challenges associated with future developments in therapeutic peptides.
[236] Signal Protein-Derived Peptides as Functional Probes and Regulators of ... — A peptide corresponding to the extreme C-terminal region of Gα subunit binds to G protein-activating region of GPCR and selectively inhibits the transduction of hormonal signal from ligand-activated receptor to its cognate G proteins, acting also as antagonist of signal transduction. The peptide, derivative of the C-terminal region of the
[238] Advance in peptide-based drug development: delivery platforms ... — It demonstrated superior performance in the SURPASS phase III trials over single receptor agonists like dulaglutide and semaglutide.18 Moreover, promising candidates are emerging, such as retaglutide for treating T2DM, fatty liver disease, and obesity by targeting the glucagon receptor (GCGR), gastric inhibitory polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R).19 Additionally, diagnostic applications like the first peptide radiopharmaceutical [68Ga]Ga-DOTA-TOC for diagnosing somatostatin receptor-positive neuroendocrine tumors (NETs) underscore the versatility of peptide-based technologies.20 To provide a clear presentation of the boom in peptide drug research, we have updated the data on marketed peptides and clinical trials from Wang et al.’s recent study2 (Table 3).
[241] Interplay of nano-based delivery systems and protein signalling in ... — The advent of nanotechnology-based drug delivery systems with therapeutic potential represents a groundbreaking frontier in the treatment of chronic respiratory diseases. ... it also includes receptor activation, signal transduction and transcription factor activity . Ex: Wnt/β-catenin pathway. ... Integration of nanotechnology with a
[242] Advances in Peptide-Decorated Targeted Drug Delivery: Exploring ... — Nanotechnology has revolutionized the fields of medicine, biomedical engineering, biotechnology, and engineering sciences over the past two decades. ... Nanobased peptide delivery systems would be of significant importance in the near future for the successful targeted and efficient delivery of peptides. This review focuses on peptide-drug
[243] SynBioNanoDesign: pioneering targeted drug delivery with engineered ... — The advent of synthetic biology, coupled with advancements in nanotechnology, has heralded a new era in the development of targeted drug delivery systems .Materials designed by synthetic biology open the possibility of creating advanced nanomaterials with tailored morphologies and functions .This review provides insight into the transformative impact of engineered nanomaterials
[259] Therapeutic peptides: current applications and future directions — Therapeutic peptides are a unique class of pharmaceutical agents composed of a series of well ... Developments in peptide drug delivery. Peptide modifications allow peptides to achieve better activity and plasma stability, and become more drug-like. ... indicating that inhibition of GCC signal transduction and NHE3 may be a suitable target for
[260] Subcellular targeting strategies for protein and peptide delivery — Subcellular targeting strategies for protein and peptide delivery - ScienceDirect Subcellular targeting strategies for protein and peptide delivery We reviewed recent advances in subcellular targeted delivery of proteins/peptides with a focus on targeting mechanisms and strategies, and highlight recent examples of active and passive organelle-specific protein and peptide delivery systems. Organelle-targeted cytosolic delivery of functional proteins and peptides enable accumulation of therapeutic proteins and peptides in a particular organelle and locally trigger the function at the action sites. We briefly summarize the functions and features of major organelles including mitochondria, nucleus, lysosome, Golgi apparatus, and endoplasmic reticulum, the targeting strategies and mechanisms for specific organelles, and examples of organelle-specific protein/peptide delivery systems (Fig. 1). Protein and peptide-based renal targeted drug delivery systems