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 PI3K Signaling

The phosphoinositide 3-kinases, PI3-kinase (PI3K), family is organized into three Classes; I, II, and III. Class I PI3-kinase is further divided into two groups: PI3K-IA and PI3K-IB. PI3-kinases phosphorylate the 3’-inositol position on a variety of membrane associated phosphatidylinositols (PI). Each class of PI3-kinase has unique preferences for phosphoinositide substrates and produces specific lipid second messengers. PI3-kinases of each group or class respond to a wide variety of signaling molecules controlled primarily by their adaptor (regulatory) subunit. Specific PI3-kinase activation and regulation potential is dependent upon the specific regulatory and catalytic isoforms that associate into the heterodimers.

Class I PI3Ks are heterodimers composed of various combinations of catalytic and regulator subunit isoforms. Class IA PI3K heterodimers contain specific isoforms of the 85 kDa adaptor subunit that facilitates interaction with receptor tyrosine kinases (RTK) and either an alpha, beta or delta p110 catalytic subunit (p110α, p110β, or p110γ). Class I PI3K regulatory subunits are derived from three genes. P85α and two alternative transcripts, p55α and p50α are derived from the gene Pik3r1. P85β is derived from gene Pik3r2. A third gene produces p55γ (p55PIK). P85α and P85β are ubiquitously expressed. The smaller isoforms are tissue specific. Class IB PI3K heterodimers contain a p101 regulatory subunit that responds to specific GPCR-associated G-protein, βγ-subunits and a gamma p110 (p110γ) catalytic subunit. Class IA and IB PI3Ks are activated by Ras-GTPase and a variety of other signaling molecules. For instance, the FGFreceptor and TrkA receptors activate PI3-kinase through the FRS-2:Grb2:Gab1 complex.

The preferred substrate of class I, PI3-kinases is phosphoinositide(4,5)bisphosphate (PIP2). This is also a substrate for members of the PI-phospholipase C family and the product of PTEN dephosphorylation of PtdIns(3,4,5)P3. Phosphorylation of PIP2 by PI3-kinase generates PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 and its 5’-dephosphorylation product, PtdIns(3,4,)P2, are important second messengers that coordinate to promote cell survival, growth, protein synthesis, mitosis, and motility. PtdIns(3,4,)P2 is also produced by Class II, PI3-kinases from PtdIns(4)P. Cell survival, mitosis, and protein synthesis are promoted by PI3-kinase-dependent activation of the PDK/AKT(PKB) pathway. PtdIns(3,4,5)P3 produced by PI3-kinase is also involved with cell motility via regulation of the Rho-GTPases, RhoA, Rac-1 and Cdc42.

Class II, PI3-kinases preferentially phosphorylates phosphatidylinositol (PI) and PtdIns(4)P to form PtdIns(3)P and PtdIns(3,4)P2, respectively. Class II, PI3-kinases also phosphorylate PtdIns(4,5)P2 in the presence of phosphatidylserine (PS). Class III, PI-kinases preferentially phosphorylate phoshatidylinositol (PtdIns) to form phosphoinositol-3-P (PtdIns(3)P). PtdIns(3)P has important roles in vesicular and protein trafficking. Class III, PI3-kinase is involved in targeting lysosomal enzymes to the endocytic pathway.