Protein Kinase B Kinases That Mediate Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Activation of Protein Kinase B

TLDR

Protein kinase B is activated by PI3K-derived lipids PtdIns(3,4,5)P3 and PtdIns(3,4)P2, but the regulation of this activation is complex across diverse signaling pathways. Binding of these lipids to PKB’s pleckstrin homology domain translocates the kinase to the membrane and permits upstream Thr308 kinases to phosphorylate it; four such PKB kinases were purified from sheep brain. The purified kinases bind PtdIns(3,4,5)P3, associate with lipid vesicles, and, when expressed heterologously, enhance receptor‑mediated PKB activation, indicating they are the primary transducers that link lipid signals to PKB‑dependent control of cell survival, glucose uptake, and glycogen metabolism.

Abstract

Protein kinase B (PKB) is activated in response to phosphoinositide 3-kinases and their lipid products phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ] and PtdIns(3,4)P 2 in the signaling pathways used by a wide variety of growth factors, antigens, and inflammatory stimuli. PKB is a direct target of these lipids, but this regulation is complex. The lipids can bind to the pleckstrin homologous domain of PKB, causing its translocation to the membrane, and also enable upstream, Thr 308 -directed kinases to phosphorylate and activate PKB. Four isoforms of these PKB kinases were purified from sheep brain. They bound PtdIns(3,4,5)P 3 and associated with lipid vesicles containing it. These kinases contain an NH 2 -terminal catalytic domain and a COOH-terminal pleckstrin homologous domain, and their heterologous expression augments receptor activation of PKB, which suggests they are the primary signal transducers that enable PtdIns(3,4,5)P 3 or PtdIns- (3,4)P 2 to activate PKB and hence to control signaling pathways regulating cell survival, glucose uptake, and glycogen metabolism.