Dual specificity phosphatases: a gene family for control of MAP kinase function

TLDR

MAP kinases mediate diverse cellular responses by being activated through dual phosphorylation, a reversible process regulated by dual‑specificity phosphatases (DSPs) that selectively dephosphorylate the critical threonine and tyrosine residues and vary in subcellular localization and isoform specificity. DSP activity is achieved by tight binding of its amino‑terminal domain to MAP kinases, which activates the phosphatase, and DSP genes are transcriptionally up‑regulated by growth factors or stress to selectively inactivate specific MAP kinase pathways.

Abstract

Mitogen-activated protein (MAP) kinases are important players in signal transduction pathways activated by a range of stimuli and mediate a number of physiological and pathological changes in cell function. MAP kinase activation requires phosphorylation on a threonine and tyrosine residue located within the activation loop of kinase subdomain VIII. This process is reversible even in the continued presence of activating stimuli, indicating that protein phosphatases provide an important mechanism for MAP kinase control. Dual specificity phosphatases (DSPs) are an emerging subclass of the protein tyrosine phosphatase (PTP) gene superfamily, which appears to be selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues within MAP kinases. Some DSPs are localized to different subcellular compartments and moreover, certain family members appear highly selective for inactivating distinct MAP kinase isoforms. This enzymatic specificity is due in part to powerful catalytic activation of the DSP phosphatase after tight binding of its amino-terminal to the target MAP kinase. DSP gene expression is induced strongly by various growth factors and/or cellular stresses, providing a sophisticated transcriptional mechanism for targeted inactivation of selected MAP kinase activities.