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

• DOI: 10.1242/jcs.01519
• Publication Date: 2004-11-24T19:33:52Z
• Authors: Xuan Li; Valerie G. Brunton; Helen R. Burgar; Lee M. Wheldon; John K. Heath
• Keywords: 0301 basic medicine; 0303 health sciences; DNA, Complementary; Indoles; Blotting, Western; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Lipid Metabolism; Phosphoproteins; Cell Line; Enzyme Activation; Mice; 03 medical and health sciences; Mutation; NIH 3T3 Cells; Animals; Humans; Immunoprecipitation; Phosphorylation; Extracellular Signal-Regulated MAP Kinases; Peptides; Adaptor Proteins, Signal Transducing; Plasmids

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.