Direct binding of Grb2 SH3 domain to FGFR2 regulates SHP2 function.
The adaptor protein Grb2 is recruited to intracellular early signalling complexes of many receptor tyrosine kinases and plays an important role transducing signals leading to MAP kinase activation. To date the SH2 domain of Grb2 has been shown to mediate receptor interactions with phosphorylated tyrosine residues sited directly on the receptor or on auxiliary docking proteins. Here we report that FGFR2 recruits Grb2 through its C-terminal SH3 domain. The binding site of this domain was mapped to the proline-rich C-terminus of the receptor. Deletion of the last 10 amino acids of FGFR2 abrogates interaction with Grb2. Synthetic peptides based on the C-terminus of FGFR2 bind to full length Grb2 with low micromolar affinity. The function of this novel mode of Grb2 binding provides resistance to site-specific Shp2-mediated receptor dephosphorylation.
Ahmed
Zamal
Z
Department of Structural & Molecular Biology, University College London, Gower Street, London, WC1E 6BT, UK.
George
Roger
R
Lin
Chi-Chuan
CC
Suen
Kin Man
KM
Levitt
James A
JA
Suhling
Klaus
K
Ladbury
John E
JE
D000595:Amino Acid Sequence; D000818:Animals; D002151:Calorimetry; D002460:Cell Line; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D018909:src Homology Domains
D051380:GRB2 Adaptor Protein; C496353:FGFR2 protein, human; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11