RAS and RHO Families of GTPases Directly Regulate Distinct Phosphoinositide 3-Kinase Isoforms

RAS proteins are important direct activators of p110α, p110γ, and p110δ type I phosphoinositide 3-kinases (PI3Ks), interacting via an amino-terminal RAS-binding domain (RBD). Here, we investigate the regulation of the ubiquitous p110β isoform of PI3K, implicated in G-protein-coupled receptor (GPCR)...

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Veröffentlicht in:Cell 2013-05, Vol.153 (5), p.1050-1063
Hauptverfasser: Fritsch, Ralph, de Krijger, Inge, Fritsch, Kornelia, George, Roger, Reason, Beth, Kumar, Madhu S., Diefenbacher, Markus, Stamp, Gordon, Downward, Julian
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Sprache:eng
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Zusammenfassung:RAS proteins are important direct activators of p110α, p110γ, and p110δ type I phosphoinositide 3-kinases (PI3Ks), interacting via an amino-terminal RAS-binding domain (RBD). Here, we investigate the regulation of the ubiquitous p110β isoform of PI3K, implicated in G-protein-coupled receptor (GPCR) signaling, PTEN-loss-driven cancers, and thrombocyte function. Unexpectedly, RAS is unable to interact with p110β, but instead RAC1 and CDC42 from the RHO subfamily of small GTPases bind and activate p110β via its RBD. In fibroblasts, GPCRs couple to PI3K through Dock180/Elmo1-mediated RAC activation and subsequent interaction with p110β. Cells from mice carrying mutations in the p110β RBD show reduced PI3K activity and defective chemotaxis, and these mice are resistant to experimental lung fibrosis. These findings revise our understanding of the regulation of type I PI3K by showing that both RAS and RHO family GTPases directly regulate distinct ubiquitous PI3K isoforms and that RAC activates p110β downstream of GPCRs. [Display omitted] •Unlike p110α, p110γ, and p110δ PI3K isoforms, RAS is unable to interact with p110β•The RHO family GTPases RAC1 and CDC42 directly bind and activate p110β via its RBD•GPCRs couple to PI3K via Dock180/Elmo1-mediated RAC activation and binding to p110β•Mice with RBD mutant p110β are resistant to experimental lung fibrosis RAS proteins bind and activate multiple PI3K isoforms. The p110β isoform of PI3K, however, is instead activated by the binding of RHO family members RAC and CDC42. Blocking this interaction blunts GPCR-mediated cellular chemotaxis and confers resistance to lung fibrosis.
ISSN:0092-8674
1097-4172
1097-4172
DOI:10.1016/j.cell.2013.04.031