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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Blotting, Western
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Cell Line
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DNA, Complementary / metabolism
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Humans
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Immunoprecipitation
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Indoles / pharmacology
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Intracellular Signaling Peptides and Proteins
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Lipid Metabolism
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Mice
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Mutation
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NIH 3T3 Cells
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Peptides / chemistry
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Phosphoproteins / metabolism
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Phosphoproteins / physiology*
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Phosphorylation
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Plasmids / metabolism
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Protein Binding
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Protein Structure, Tertiary
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Proteins / metabolism*
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Receptors, Fibroblast Growth Factor / metabolism*
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Signal Transduction
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Sulfonamides / pharmacology
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Time Factors
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Transfection
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Tyrosine / chemistry
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Tyrosine / metabolism
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src-Family Kinases / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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DNA, Complementary
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FRS2 protein, human
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Indoles
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Peptides
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Phosphoproteins
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Proteins
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Receptors, Fibroblast Growth Factor
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SPRY2 protein, human
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SU 6656
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Sulfonamides
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Tyrosine
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src-Family Kinases
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Extracellular Signal-Regulated MAP Kinases