The p110 isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110

Center for Cell Signaling, Institute of Cancer, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2008; 105(24):8292-7. DOI: 10.1073/pnas.0707761105
Source: PubMed


The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110alpha, p110beta, and p110delta) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110alpha and p110delta to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110gamma class IB PI3K lack SH2 domains and instead couple p110gamma to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110beta and cells derived from a p110beta-deficient mouse line, that p110beta is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110beta and p110gamma contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110beta but not p110gamma, p110beta mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1-phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110gamma in these cells reduced the contribution of p110beta to GPCR signaling. Taken together, these data show that p110beta and p110gamma can couple redundantly to the same GPCR agonists. p110beta, which shows a much broader tissue distribution than the leukocyte-restricted p110gamma, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110gamma expression is low or absent.

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    • "Class IA PI3K consists of three isoforms of catalytic subunit, p110α, p110β, and p110δ, which are activated by receptor tyrosine kinases such as VEGFR2, whereas class IB p110γ is activated by GPCR[48]. HUVECs express p110α and p110β as major forms and p110δ at a very low level[49], and p110β is functionally redundant with p110γ in endothelial cells[48,49]. Our Fig 5.Inhibitory effects of BJ-1108 on human breast cancer cells (MDA-MB-231 and MCF-7)-induced angiogenesis and tumor growth. "

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    • "Class IA PI3K consists of three isoforms of catalytic subunit, p110α, p110β, and p110δ, which are activated by receptor tyrosine kinases such as VEGFR2, whereas class IB p110γ is activated by GPCR [48]. HUVECs express p110α and p110β as major forms and p110δ at a very low level [49], and p110β is functionally redundant with p110γ in endothelial cells [48, 49]. Our BJ-1108 Inhibits Serotonin-Induced Angiogenesis through PI3K/NOX Pathway current data showing that BJ-1108 suppressed PI3K p110β activity in an enzyme assay as well as 5-HT-induced PI3K phosphorylation suggest that BJ-1108 may be a broad spectrum antiangiogenic agent inhibiting a common signaling molecule downstream of receptor tyrosine kinases and GPCRs upon activation by angiogenic stimuli. "
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