c-Src is involved in regulating signal transmission from PDGFbeta receptor-GPCR(s) complexes in mammalian cells

Waters, Catherine M and Connell, Michelle C and Pyne, Susan and Pyne, Nigel J (2005) c-Src is involved in regulating signal transmission from PDGFbeta receptor-GPCR(s) complexes in mammalian cells. Cellular Signalling, 17 (2). pp. 263-277. ISSN 1873-3913

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Abstract

We have reported that the platelet-derived growth factor receptor-beta (PDGFbeta) forms a novel signaling complex with G protein-coupled receptors (GPCR) (e.g. S1P(1) receptor) that enables more efficient activation of p42/p44 mitogen-activated protein kinase (MAPK) in response to PDGF and sphingosine 1-phosphate (S1P). We now demonstrate that c-Src participates in regulating the endocytosis of PDGFbeta receptor-GPCR complexes in response to PDGF. This leads to association of cytoplasmic p42/p44 MAPK with the receptor complex in endocytic vesicles. c-Src is regulated by G protein betagamma subunits and can interact with beta-arrestin. Indeed, the PDGF-dependent activation of p42/p44 MAPK was reduced by over-expression of the C-terminal domain of GRK2 (sequesters Gbetagamma subunits), the clathrin-binding domain of beta-arrestin and by inhibitors of c-Src and clathrin-mediated endocytosis. Moreover, PDGF and S1P induce the recruitment of c-Src to the PDGFbeta receptor-S1P(1) receptor complex. This leads to a G protein/c-Src-dependent tyrosine phosphorylation of Gab1 and accumulation of dynamin II at the plasma membrane, a step required for endocytosis of the PDGFbeta receptor-GPCR complex. These findings provide important information concerning the molecular organisation of novel receptor tyrosine kinase (RTK)-GPCR signal relays in mammalian cells.

Author(s):Waters, Catherine M, Connell, Michelle C, Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584 and Pyne, Nigel J ORCID logoORCID: https://orcid.org/0000-0002-5657-4578
Item type:Article
ID code:34972
Keywords:adaptor proteins, signal transducing, animals, arrestins, cadaverine, cell line, cells, cultured, concanavalin A, cyclic AMP-dependent protein kinases, dynamin II, endocytosis, enzyme inhibitors, GRB2 adaptor protein, guinea pigs, humans, immunoprecipitation, lysophospholipids, mitogen-activated protein kinase 1, mitogen-activated protein kinase 3, myocytes, smooth muscle, pertussis toxin, phosphatidylinositol 3-kinases, phosphoproteins, phosphorylation, platelet-derived growth factor, proto-oncogene proteins pp60(c-src), pyrimidines, receptor, platelet-derived Growth Factor beta, receptors, G-protein-coupled, signal transduction, sphingosine, transfection, tansport vesicles, beta-adrenergic receptor kinases, Pharmacy and materia medica, Cell Biology
Subjects:Medicine > Pharmacy and materia medica
Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Depositing user: Pure Administrator
Date deposited:11 Nov 2011 16:38
Last modified:17 Jan 2020 07:12
URI:https://strathprints.strath.ac.uk/id/eprint/34972
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