%0 Journal Article %1 Slupsky1999 %A Slupsky, J. R. %A Quitterer, U. %A Weber, C. K. %A Gierschik, P. %A Lohse, M. J. %A Rapp, U. R. %D 1999 %J Curr Biol %K Animals B2 Binding Bradykinin Bradykinin/genetics/physiology COS Cell Cercopithecus Fusion GTP-Binding Heterotrimeric Humans Kidney Kinase Line MAP Protein Proteins Proteins/physiology Proto-Oncogene Recombinant Signaling System/*physiology Transfection aethiops c-raf/*metabolism p21(ras)/physiology Receptor Proteins/metabolism %N 17 %P 971-4 %T Binding of Gbetagamma subunits to cRaf1 downregulates G-protein-coupled receptor signalling %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10508586 %V 9 %X Receptors of the seven transmembrane domain family are coupled to heterotrimeric G proteins 1. Binding of ligand to these receptors induces dissociation of the heterotrimeric complex into free GTP-Galpha and Gbetagamma subunits, which then interact with their respective effector molecules to stimulate specific cellular responses. In some cases, these cellular responses involve mitogenic signalling 2. The mitogen-activated protein (MAP) kinase cascade is initiated by the protein kinase cRaf1 and links growth factor receptor signalling to cell growth and differentiation 3. The main activator of cRaf1 is the small GTP-binding protein Ras 4, and the binding of cRaf1 to GTP-Ras translocates cRaf1 to the plasma membrane, where it is activated 5. It has been reported that cRaf1 associates directly with the beta subunit of heterotrimeric G proteins in vitro, and with the betagamma subunit complex in vivo 6, but the role of this association is not yet understood. Here, we show that cRaf1 associates with Gbeta1gamma2, and that this association in mammalian cells is significantly enhanced when active p21(Ras) is present or when cRaf1 is otherwise targeted to the membrane. Association with Gbeta1gamma2 has no effect on the kinase activity of cRaf1, but cRaf1 can affect Gbetagamma-mediated signalling events. Thus, membrane-localised cRaf1 inhibits G-protein-coupled receptor (GPCR)-stimulated activation of phospholipase Cbeta (PLCbeta) by sequestration of Gbetagamma subunits, an effect also observed with endogenous levels of cRaf1. Our data suggest that cRaf1 may be an important regulator of signalling by Gbetagamma, particularly in those GPCR systems that stimulate the MAP kinase cascade through the activation of p21(Ras).

@article{Slupsky1999, abstract = {Receptors of the seven transmembrane domain family are coupled to heterotrimeric G proteins [1]. Binding of ligand to these receptors induces dissociation of the heterotrimeric complex into free GTP-Galpha and Gbetagamma subunits, which then interact with their respective effector molecules to stimulate specific cellular responses. In some cases, these cellular responses involve mitogenic signalling [2]. The mitogen-activated protein (MAP) kinase cascade is initiated by the protein kinase cRaf1 and links growth factor receptor signalling to cell growth and differentiation [3]. The main activator of cRaf1 is the small GTP-binding protein Ras [4], and the binding of cRaf1 to GTP-Ras translocates cRaf1 to the plasma membrane, where it is activated [5]. It has been reported that cRaf1 associates directly with the beta subunit of heterotrimeric G proteins in vitro, and with the betagamma subunit complex in vivo [6], but the role of this association is not yet understood. Here, we show that cRaf1 associates with Gbeta1gamma2, and that this association in mammalian cells is significantly enhanced when active p21(Ras) is present or when cRaf1 is otherwise targeted to the membrane. Association with Gbeta1gamma2 has no effect on the kinase activity of cRaf1, but cRaf1 can affect Gbetagamma-mediated signalling events. Thus, membrane-localised cRaf1 inhibits G-protein-coupled receptor (GPCR)-stimulated activation of phospholipase Cbeta (PLCbeta) by sequestration of Gbetagamma subunits, an effect also observed with endogenous levels of cRaf1. Our data suggest that cRaf1 may be an important regulator of signalling by Gbetagamma, particularly in those GPCR systems that stimulate the MAP kinase cascade through the activation of p21(Ras).}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Slupsky, J. R. and Quitterer, U. and Weber, C. K. and Gierschik, P. and Lohse, M. J. and Rapp, U. R.}, biburl = {https://www.bibsonomy.org/bibtex/2f97743ee71a32159cf8bb9d352ce85c3/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {04b2e0ec88e6785f8c8189d4e8c3f9c8}, intrahash = {f97743ee71a32159cf8bb9d352ce85c3}, issn = {0960-9822 (Print) 0960-9822 (Linking)}, journal = {Curr Biol}, keywords = {Animals B2 Binding Bradykinin Bradykinin/genetics/physiology COS Cell Cercopithecus Fusion GTP-Binding Heterotrimeric Humans Kidney Kinase Line MAP Protein Proteins Proteins/physiology Proto-Oncogene Recombinant Signaling System/*physiology Transfection aethiops c-raf/*metabolism p21(ras)/physiology Receptor Proteins/metabolism}, month = {Sep 9}, note = {Slupsky, J R Quitterer, U Weber, C K Gierschik, P Lohse, M J Rapp, U R Research Support, Non-U.S. Gov't England Current biology : CB Curr Biol. 1999 Sep 9;9(17):971-4.}, number = 17, pages = {971-4}, shorttitle = {Binding of Gbetagamma subunits to cRaf1 downregulates G-protein-coupled receptor signalling}, timestamp = {2010-12-14T18:21:43.000+0100}, title = {Binding of Gbetagamma subunits to cRaf1 downregulates G-protein-coupled receptor signalling}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10508586}, volume = 9, year = 1999 }