Phosphoinositide 3-kinase alpha (p110α-p85β) (PI3Kα (p110α/p85β))

The PI3K p110α-p85β holoenzyme is a specific isoform of the Class IA phosphoinositide 3-kinase (PI3K) complex, consisting of the p110α catalytic subunit (encoded by PIK3CA) and the p85β regulatory subunit (encoded by PIK3R2) (UniProt P42336, O00459). This enzyme complex is a central node in the PI3K/AKT/mTOR signaling pathway, which is triggered by receptor tyrosine kinases to regulate essential cellular functions such as growth, metabolism, and survival (Fruman et al., Cell 2017, PMID: 28802037). The p85β subunit plays a dual role by stabilizing the p110α subunit and inhibiting its basal activity, while also facilitating its recruitment to the plasma membrane upon activation (He et al., Nature Communications 2021, PMID: 33859189). Gain-of-function mutations in PIK3CA or alterations in PIK3R2 are frequently observed in human cancers, particularly breast and endometrial malignancies, leading to constitutive pathway activation and oncogenic transformation. Additionally, germline or somatic mutations in these subunits are linked to developmental overgrowth disorders like PIK3CA-related overgrowth spectrum (PROS) and MPPH syndrome (NIH/GARD). Therapeutic strategies targeting this holoenzyme focus on alpha-selective inhibitors like alpelisib, which aim to block the catalytic activity of p110α to inhibit tumor progression (FDA Label: Piqray). However, because PI3Kα is a primary mediator of insulin signaling, its pharmacological inhibition often results in metabolic side effects, most notably hyperglycemia.

Other names

PI3K p110alpha/p85betaPIK3CA/PIK3R2 complexPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha/regulatory subunit 2Class IA PI3K alpha (p85β isoform)p110α:p85β holoenzyme

Competitive inhibition of the ATP-binding site on the p110α catalytic subunit, preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3).