title: RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms.
abstract: 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.
authors.affiliation: Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Ralph
authors.initials: R
authors.lastname: Fritsch
authors.forename: Inge
authors.initials: I
authors.lastname: de Krijger
authors.forename: Kornelia
authors.initials: K
authors.lastname: Fritsch
authors.forename: Roger
authors.initials: R
authors.lastname: George
authors.forename: Beth
authors.initials: B
authors.lastname: Reason
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Kumar
authors.forename: Markus
authors.initials: M
authors.lastname: Diefenbacher
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: D000818:Animals; D002633:Chemotaxis; D058534:Class I Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000139:chemically induced / Q000517:prevention & control; D020555:GTP-Binding Protein Regulators / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C484092:Cdc42ep5 protein, mouse; D020555:GTP-Binding Protein Regulators; D020662:Guanine Nucleotide Exchange Factors; D007527:Isoenzymes; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins