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

Catherine M Waters, Michelle C Connell, Susan Pyne, Nigel J Pyne

Research output: Contribution to journalArticle

70 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)263-277
Number of pages15
JournalCellular Signalling
Volume17
Issue number2
Early online date15 Sep 2004
DOIs
Publication statusPublished - Feb 2005

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

Cite this