Document Detail

c-Src is involved in regulating signal transmission from PDGFbeta receptor-GPCR(s) complexes in mammalian cells.
MedLine Citation:
PMID:  15494217     Owner:  NLM     Status:  MEDLINE    
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.
Catherine M Waters; Michelle C Connell; Susan Pyne; Nigel J Pyne
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cellular signalling     Volume:  17     ISSN:  0898-6568     ISO Abbreviation:  Cell. Signal.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2004-10-20     Completed Date:  2005-04-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8904683     Medline TA:  Cell Signal     Country:  England    
Other Details:
Languages:  eng     Pagination:  263-77     Citation Subset:  IM    
Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, 27 Taylor St., Glasgow G4 ONR, UK.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / metabolism
Adaptor Proteins, Signal Transducing / genetics,  metabolism
Arrestins / genetics,  metabolism
Cadaverine / analogs & derivatives*,  pharmacology
Cell Line
Cells, Cultured
Concanavalin A / pharmacology
Cyclic AMP-Dependent Protein Kinases / genetics,  metabolism
Dynamin II / metabolism
Endocytosis / drug effects
Enzyme Inhibitors / pharmacology
GRB2 Adaptor Protein
Guinea Pigs
Lysophospholipids / pharmacology
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Myocytes, Smooth Muscle / drug effects,  metabolism,  physiology
Pertussis Toxin / pharmacology
Phosphoproteins / metabolism
Phosphorylation / drug effects
Platelet-Derived Growth Factor / pharmacology
Proto-Oncogene Proteins pp60(c-src) / metabolism,  physiology*
Pyrimidines / pharmacology
Receptor, Platelet-Derived Growth Factor beta / genetics,  metabolism,  physiology*
Receptors, G-Protein-Coupled / genetics,  metabolism,  physiology*
Receptors, Lysosphingolipid / genetics,  metabolism
Signal Transduction / drug effects,  physiology*
Sphingosine / analogs & derivatives*,  pharmacology
Transport Vesicles / chemistry,  metabolism
beta-Adrenergic Receptor Kinases
Reg. No./Substance:
0/AG 1879; 0/Adaptor Proteins, Signal Transducing; 0/Arrestins; 0/Enzyme Inhibitors; 0/GAB1 protein, human; 0/GRB2 Adaptor Protein; 0/GRB2 protein, human; 0/Lysophospholipids; 0/Phosphoproteins; 0/Platelet-Derived Growth Factor; 0/Pyrimidines; 0/Receptors, G-Protein-Coupled; 0/Receptors, Lysosphingolipid; 0/beta-arrestin; 10121-91-2/monodansylcadaverine; 11028-71-0/Concanavalin A; 123-78-4/Sphingosine; 26993-30-6/sphingosine 1-phosphate; 462-94-2/Cadaverine; EC Toxin; EC 3-Kinase; EC, Platelet-Derived Growth Factor beta; EC Proteins pp60(c-src); EC AMP-Dependent Protein Kinases; EC Receptor Kinases; EC Protein Kinase 1; EC Protein Kinase 3; EC II

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