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The PTB domain of ShcA couples receptor activation to the cytoskeletal regulator IQGAP1
Author(s) -
Smith Matthew J,
Hardy W Rod,
Li GuangYao,
Goudreault Marilyn,
Hersch Steven,
Metalnikov Pavel,
Starostine Andrei,
Pawson Tony,
Ikura Mitsuhiko
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.399
Subject(s) - iqgap1 , signal transducing adaptor protein , grb2 , microbiology and biotechnology , phosphotyrosine binding domain , cytoskeleton , biology , scaffold protein , receptor , signal transduction , sh2 domain , biochemistry , proto oncogene tyrosine protein kinase src , cell
Adaptor proteins respond to stimuli and recruit downstream complexes using interactions conferred by associated protein domains and linear motifs. The ShcA adaptor contains two phosphotyrosine recognition modules responsible for binding activated receptors, resulting in the subsequent recruitment of Grb2 and activation of Ras/MAPK. However, there is evidence that Grb2‐independent signalling from ShcA has an important role in development. Using mass spectrometry, we identified the multidomain scaffold IQGAP1 as a ShcA‐interacting protein. IQGAP1 and ShcA co‐precipitate and are co‐recruited to membrane ruffles induced by activated receptors of the ErbB family, and a reduction in ShcA protein levels inhibits the formation of lamellipodia. We used NMR to characterize a direct, non‐canonical ShcA PTB domain interaction with a helical fragment from the IQGAP1 N‐terminal region that is pTyr‐independent. This interaction is mutually exclusive with binding to a more conventional PTB domain peptide ligand from PTP–PEST. ShcA‐mediated recruitment of IQGAP1 may have an important role in cytoskeletal reorganization downstream of activated receptors at the cell surface.