Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival.
Class Ia phosphoinositide (PI) 3-kinase is a central component in growth factor signaling and is comprised of a p110 catalytic subunit and a regulatory subunit, the most common family of which is derived from the p85alpha gene (Pik3r1). Optimal signaling through the PI 3-kinase pathway depends on a critical molecular balance between the regulatory and catalytic subunits. In wild-type cells, the p85 subunit is more abundant than p110, leading to competition between the p85 monomer and the p85-p110 dimer and ineffective signaling. Heterozygous disruption of Pik3r1 results in increased Akt activity and decreased apoptosis by insulin-like growth factor 1 (IGF-1) through up-regulated phosphatidylinositol (3,4,5)-triphosphate production. Complete depletion of p85alpha, on the other hand, results in significantly increased apoptosis due to reduced PI 3-kinase-dependent signaling. Thus, a reduction in p85alpha represents a novel therapeutic target for enhancing IGF-1/insulin signaling, prolongation of cell survival, and protection against apoptosis.
Ueki
Kohjiro
K
Research Division, Joslin Diabetes Center, Harvard Medical School. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Fruman
David A
DA
Brachmann
Saskia M
SM
Tseng
Yu-Hua
YH
Cantley
Lewis C
LC
Kahn
C Ronald
CR
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D019281:Dimerization; D018390:Gene Targeting; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D021122:Protein Subunits; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; D021122:Protein Subunits; C060974:phosphatidylinositol 3,4,5-triphosphate; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases