Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10816522 | Cellular Signalling | 2005 | 15 Pages |
Abstract
We have reported that the platelet-derived growth factor receptor-beta (PDGFβ) forms a novel signaling complex with G protein-coupled receptors (GPCR) (e.g. S1P1 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 PDGFβ 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 βγ subunits and can interact with β-arrestin. Indeed, the PDGF-dependent activation of p42/p44 MAPK was reduced by over-expression of the C-terminal domain of GRK2 (sequesters Gβγ subunits), the clathrin-binding domain of β-arrestin and by inhibitors of c-Src and clathrin-mediated endocytosis. Moreover, PDGF and S1P induce the recruitment of c-Src to the PDGFβ receptor-S1P1 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 PDGFβ receptor-GPCR complex. These findings provide important information concerning the molecular organisation of novel receptor tyrosine kinase (RTK)-GPCR signal relays in mammalian cells.
Keywords
PDGFβRGRKPDGFLPAPI3KGPCRGRB-2MDCASMRAFRASInhibitory G proteinHEKConcanavalin AG protein-coupled receptor kinaseMAPKlysophosphatidic acidCon AChoImmunoprecipitationChinese Hamster OvaryAirway smooth muscleplatelet-derived growth factorphosphoinositide 3-kinasemitogen-activated protein kinaseSerine/threonine protein kinasehuman embryonic kidneyGab1GiαG protein-coupled receptor
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Biochemistry
Authors
Catherine M. Waters, Michelle C. Connell, Susan Pyne, Nigel J. Pyne,