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

69 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

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Platelet-Derived Growth Factor beta Receptor
G-Protein-Coupled Receptors
Mitogen-Activated Protein Kinase 1
Endocytosis
Lysosphingolipid Receptors
Clathrin
GTP-Binding Proteins
Dynamin II
Transport Vesicles
Protein Subunits
Receptor Protein-Tyrosine Kinases
Tyrosine
Phosphorylation
Cell Membrane
sphingosine 1-phosphate
beta-Arrestins

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

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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.",
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author = "Waters, {Catherine M} and Connell, {Michelle C} and Susan Pyne and Pyne, {Nigel J}",
year = "2005",
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journal = "Cellular Signalling",
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c-Src is involved in regulating signal transmission from PDGFbeta receptor-GPCR(s) complexes in mammalian cells. / Waters, Catherine M; Connell, Michelle C; Pyne, Susan; Pyne, Nigel J.

In: Cellular Signalling, Vol. 17, No. 2, 02.2005, p. 263-277.

Research output: Contribution to journalArticle

TY - JOUR

T1 - c-Src is involved in regulating signal transmission from PDGFbeta receptor-GPCR(s) complexes in mammalian cells

AU - Waters, Catherine M

AU - Connell, Michelle C

AU - Pyne, Susan

AU - Pyne, Nigel J

PY - 2005/2

Y1 - 2005/2

N2 - 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.

AB - 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.

KW - adaptor proteins, signal transducing

KW - animals

KW - arrestins

KW - cadaverine

KW - cell line

KW - cells, cultured

KW - concanavalin A

KW - cyclic AMP-dependent protein kinases

KW - dynamin II

KW - endocytosis

KW - enzyme inhibitors

KW - GRB2 adaptor protein

KW - guinea pigs

KW - humans

KW - immunoprecipitation

KW - lysophospholipids

KW - mitogen-activated protein kinase 1

KW - mitogen-activated protein kinase 3

KW - myocytes, smooth muscle

KW - pertussis toxin

KW - phosphatidylinositol 3-kinases

KW - phosphoproteins

KW - phosphorylation

KW - platelet-derived growth factor

KW - proto-oncogene proteins pp60(c-src)

KW - pyrimidines

KW - receptor, platelet-derived Growth Factor beta

KW - receptors, G-protein-coupled

KW - signal transduction

KW - sphingosine

KW - transfection

KW - tansport vesicles

KW - beta-adrenergic receptor kinases

U2 - 10.1016/j.cellsig.2004.07.011

DO - 10.1016/j.cellsig.2004.07.011

M3 - Article

VL - 17

SP - 263

EP - 277

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 2

ER -