title: Coordinated activation of the Rac-GAP β2-chimaerin by an atypical proline-rich domain and diacylglycerol.
abstract: Chimaerins, a family of GTPase activating proteins for the small G-protein Rac, have been implicated in development, neuritogenesis and cancer. These Rac-GTPase activating proteins are regulated by the lipid second messenger diacylglycerol generated by tyrosine kinases such as the epidermal growth factor receptor. Here we identify an atypical proline-rich motif in chimaerins that binds to the adaptor protein Nck1. Unlike most Nck1 partners, chimaerins bind to the third SH3 domain of Nck1. This association is mediated by electrostatic interactions of basic residues within the Pro-rich motif with acidic clusters in the SH3 domain. Epidermal growth factor promotes the binding of β2-chimaerin to Nck1 in the cell periphery in a diacylglycerol-dependent manner. Moreover, β2-chimaerin translocation to the plasma membrane and its peripheral association with Rac1 requires Nck1. Our studies underscore a coordinated mechanism for β2-chimaerin activation that involves lipid interactions via the C1 domain and protein-protein interactions via the N-terminal proline-rich region.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Gutierrez-Uzquiza
authors.forename: Francheska
authors.initials: F
authors.lastname: Colon-Gonzalez
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Leonard
authors.forename: Bertram J
authors.initials: BJ
authors.lastname: Canagarajah
authors.forename: HongBin
authors.initials: H
authors.lastname: Wang
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Mayer
authors.forename: James H
authors.initials: JH
authors.lastname: Hurley
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Kazanietz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D004075:Diglycerides / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D055232:Proline-Rich Protein Domains; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013329:Structure-Activity Relationship; D014638:Vanadates / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: C011439:1,2-diacylglycerol; D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D004075:Diglycerides; D020690:GTPase-Activating Proteins; C078332:Nck protein; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; C079844:beta-chimaerin; C076715:pervanadate; D014638:Vanadates; D004815:Epidermal Growth Factor; D020744:rac GTP-Binding Proteins