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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 24; p. 8292
• Main Authors: Guillermet-Guibert, Julie, Bjorklof, Katja, Salpekar, Ashreena, Gonella, Cristiano, Ramadani, Faruk, Bilancio, Antonio, Meek, Stephen, Smith, Andrew J H, Okkenhaug, Klaus, Vanhaesebroeck, Bart
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 17.06.2008
• Subjects: Kinases; Leukocytes; Proteins; Rodents; T cell receptors
• ISSN: 0027-8424; 1091-6490

The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110α, p110β, and p110...) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110α and p110... to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110... class IB PI3K lack SH2 domains and instead couple p110... to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110β and cells derived from a p110β-deficient mouse line, that p110β is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110β and p110... 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 p110β but not p110..., p110β 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 p110... in these cells reduced the contribution of p110β to GPCR signaling. Taken together, these data show that p110β and p110... can couple redundantly to the same GPCR agonists. p110β, which shows a much broader tissue distribution than the leukocyte-restricted p110..., could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110... expression is low or absent. (ProQuest: ... denotes formulae/symbols omitted.)