PIK3R1

PIK3R1 encodes p85α (and, via alternative promoters/splicing, the shorter p55α and p50α), the regulatory subunit of class IA phosphatidylinositol 3-kinase (PI3K). p85α is a non-catalytic, multidomain adaptor/regulatory protein (SH3, proline-rich, BCR/RhoGAP-homology (BH), and nSH2–iSH2–cSH2 modules). Its inter-SH2 coiled coil binds and stabilizes the otherwise-unstable p110 catalytic subunit (PIK3CA/PIK3CB/PIK3CD), forming an obligate heterodimer, while its SH2 domains restrain basal lipid-kinase activity. Upon growth-factor/insulin stimulation, the two SH2 domains dock tyrosine-phosphorylated YXXM motifs on activated receptor tyrosine kinases and on adaptor/scaffold proteins such as IRS1/2, thereby relieving autoinhibition and recruiting the heterodimer to the cytoplasmic face of receptor-bearing membranes; there the associated p110 phosphorylates PI(4,5)P2 to PI(3,4,5)P3, initiating AKT-centered signaling that controls growth, survival, proliferation, metabolism (including insulin-stimulated glucose uptake), cytoskeletal remodeling and vesicular trafficking. p85α is chiefly cytosolic at rest and is recruited to membranes on activation; it also has p110-independent roles, including modulation of the ER-stress/unfolded protein response through interaction with XBP1. Human loss-of-function or dominant variants cause SHORT syndrome, agammaglobulinemia and immunodeficiency with lymphoproliferation, and somatic variants occur in cancers and vascular malformations.

Disorders

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