FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity

J Cell Sci. 2004 Dec 1;117(Pt 25):6007-17. doi: 10.1242/jcs.01519.

Abstract

Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human Sprouty 2 (hSpry2) on residue Y55. This event requires the presence of the signalling adaptor fibroblast growth factor receptor substrate 2 (FRS2). The phosphorylation of hSpry2 is therefore mediated by an intermediate kinase. Using a SRC family kinase-specific inhibitor and mutant cells, we show that hSpry2 is a direct substrate for SRC family kinases, including SRC itself. Activation of SRC via fibroblast growth factor signalling is dependent upon FRS2 and fibroblast growth factor receptor kinase activity. SRC forms a complex with hSpry2 and this interaction is enhanced by hSpry2 phosphorylation. Phosphorylation of hSpry2 is required for hSpry2 to inhibit activation of the extracellular signal-regulated kinase pathway. These results show that recruitment of SRC to FRS2 leads to activation of signal attenuation pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Blotting, Western
  • Cell Line
  • DNA, Complementary / metabolism
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Immunoprecipitation
  • Indoles / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Lipid Metabolism
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Peptides / chemistry
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / metabolism*
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Time Factors
  • Transfection
  • Tyrosine / chemistry
  • Tyrosine / metabolism
  • src-Family Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA, Complementary
  • FRS2 protein, human
  • Indoles
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Peptides
  • Phosphoproteins
  • Proteins
  • Receptors, Fibroblast Growth Factor
  • SPRY2 protein, human
  • SU 6656
  • Sulfonamides
  • Tyrosine
  • src-Family Kinases
  • Extracellular Signal-Regulated MAP Kinases