pik3r1

PIK3R1 is a gene that encodes the regulatory subunit p85 alpha of class IA phosphoinositide 3-kinases (PI3Ks). The p85α protein forms heterodimers with the catalytic subunits p110α, p110β, and p110δ, and it contains domains including SH3 and two SH2 domains (nSH2 and cSH2) adjacent to an inter-SH2 region that binds the p110 subunit. The SH2 domains also mediate binding to phosphotyrosine motifs on activated receptors and adaptor proteins.

Functionally, p85α acts as a regulator of the p110 catalytic subunits. In resting cells, it helps stabilize p110 and keep PI3K activity restrained. Upon engagement of receptor tyrosine kinases or other adaptor proteins, the SH2 domains recruit the PI3K complex to the membrane, where p110 phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). This lipid second messenger promotes recruitment and activation of AKT and other downstream effectors, propagating signals that control cell growth, survival, metabolism, and migration.

PIK3R1 produces multiple regulatory isoforms through alternative splicing, including p85α, p55α, and p50α, which have distinct tissue distributions and regulatory properties. The gene is located on chromosome 5 and is widely expressed, with activity contributing to signaling downstream of many receptor pathways such as insulin, growth factors, and cytokines.

Clinical significance includes inherited mutations in PIK3R1 associated with SHORT syndrome, a disorder characterized by growth retardation and insulin resistance. Somatic alterations in PIK3R1 have been identified in various cancers and hematologic malignancies, often contributing to dysregulated PI3K signaling and altered cellular responses.