Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 24, Pages 8292-8297Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0707761105
Keywords
gene targeting; signaling; tyrosine kinase; Akt; insulin
Categories
Funding
- Biotechnology and Biological Sciences Research Council [BB/C509890/1, BBS/E/B/0000M979, BB/C505659/1, BBS/E/B/0000C236, BB/C505659/2] Funding Source: researchfish
- Medical Research Council [G0700711B] Funding Source: researchfish
- BBSRC [BBS/E/B/0000C236] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C50989/1, BB/C505659/2, BB/C505659/1, BBS/E/B/0000M979, BBS/E/B/0000C236, BB/C509890/1] Funding Source: Medline
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The p110 isoforms of phosphoinositide,3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic sub-units (p110 alpha, p110 beta, and p110 delta) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110 alpha and p110 delta to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110 gamma class IB PI3K lack SH2 domains and instead couple p110 gamma to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110 beta and cells derived from a p110 beta-deficient mouse line, that p110 beta is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110 beta and p110 gamma 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 p110 beta but not p110 gamma, p110 beta 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 gamma in these cells reduced the contribution of p110 beta to GPCR signaling. Taken together, these data show that p110 beta and p110 gamma can couple redundantly to the same GPCR agonists. p110 beta, which shows a much broader tissue distribution than the leukocyterestricted p110 gamma, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110 gamma expression is low or absent.
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