PIK3R5 encodes the regulatory subunit 5 of phosphoinositide-3-kinase gamma (PI3Kγ), a critical component of the PI3K/AKT signaling pathway. As a regulatory subunit of the PI3Kγ complex, PIK3R5 is required for recruitment of the catalytic subunit to the plasma membrane through interaction with beta-gamma G protein dimers, enabling G protein-coupled receptor-mediated activation 1. The protein functions in positive regulation of PI3K/AKT signaling and participates in immune responses and MAP kinase pathway activation.
Mechanistically, PIK3R5 stabilizes the active PI3Kγ enzymatic complex and enables noncanonical substrate phosphorylation, including phosphorylation of PAK1, which regulates mitochondrial oxidative phosphorylation 1. The gene is particularly active in myeloid-restricted tissues, where the PIK3CG/p110γ-PIK3R5/p101 axis plays essential roles in cell fitness 2.
Disease relevance includes: (1) Ataxia-oculomotor apraxia type 3 (AOA3), caused by missense mutations affecting cerebellar development 3; (2) acute leukemias and myeloid leukemias, where PIK3R5 activation drives cancer cell dependencies amenable to selective PI3Kγ inhibition 12; (3) septic myocardial injury, where PIK3R5 functions as a hub gene in inflammatory responses 4; (4) steroid-induced femoral head necrosis, where promoter methylation silences PIK3R5 and impairs PI3K/AKT signaling 5; and (5) polyomavirus infections, where PIK3R5 facilitates intracellular viral entry 6. Clinically, PIK3R5-selective targeting shows promise in leukemia treatment and may benefit infectious disease management.
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Disease relevance includes: (1) Ataxia-oculomotor apraxia type 3 (AOA3), caused by missense mutations affecting cerebellar development ; (2) acute leukemias and myeloid leukemias, where PIK3R5 activation drives cancer cell dependencies amenable to selective PI3Kγ inhibition , ; (3) septic myocardial injury, where PIK3R5 functions as a hub gene in inflammatory responses ; (4) steroid-induced femoral head necrosis, where promoter methylation silences PIK3R5 and impairs PI3K/AKT signaling ; and (5) polyomavirus infections, where PIK3R5 facilitates intracellular viral entry .
PMID: 220655244
Disease relevance includes: (1) Ataxia-oculomotor apraxia type 3 (AOA3), caused by missense mutations affecting cerebellar development ; (2) acute leukemias and myeloid leukemias, where PIK3R5 activation drives cancer cell dependencies amenable to selective PI3Kγ inhibition , ; (3) septic myocardial injury, where PIK3R5 functions as a hub gene in inflammatory responses ; (4) steroid-induced femoral head necrosis, where promoter methylation silences PIK3R5 and impairs PI3K/AKT signaling ; and (5) polyomavirus infections, where PIK3R5 facilitates intracellular viral entry .
PMID: 379182805
Disease relevance includes: (1) Ataxia-oculomotor apraxia type 3 (AOA3), caused by missense mutations affecting cerebellar development ; (2) acute leukemias and myeloid leukemias, where PIK3R5 activation drives cancer cell dependencies amenable to selective PI3Kγ inhibition , ; (3) septic myocardial injury, where PIK3R5 functions as a hub gene in inflammatory responses ; (4) steroid-induced femoral head necrosis, where promoter methylation silences PIK3R5 and impairs PI3K/AKT signaling ; and (5) polyomavirus infections, where PIK3R5 facilitates intracellular viral entry .
PMID: 377092446
Disease relevance includes: (1) Ataxia-oculomotor apraxia type 3 (AOA3), caused by missense mutations affecting cerebellar development ; (2) acute leukemias and myeloid leukemias, where PIK3R5 activation drives cancer cell dependencies amenable to selective PI3Kγ inhibition , ; (3) septic myocardial injury, where PIK3R5 functions as a hub gene in inflammatory responses ; (4) steroid-induced femoral head necrosis, where promoter methylation silences PIK3R5 and impairs PI3K/AKT signaling ; and (5) polyomavirus infections, where PIK3R5 facilitates intracellular viral entry .
PMID: 33092168