The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor.

Molecular and Cellular Biology
A G BatzerB Margolis

Abstract

Shc is an SH2 domain protein that is tyrosine phosphorylated in cells stimulated with a variety of growth factors and cytokines. Once phosphorylated, Shc binds the Grb2-Sos complex, leading to Ras activation. Shc can interact with tyrosine-phosphorylated proteins by binding to phosphotyrosine in the context of an NPXpY motif, where pY is a phosphotyrosine. This is an unusual binding site for an SH2 domain protein whose binding specificity is usually controlled by residues carboxy terminal, not amino terminal, to the phosphotyrosine. Recently we identified a second region in Shc, named the phosphotyrosine interaction (PI) domain, and we have found it to be present in a variety of other cellular proteins. In this study we used a dephosphorylation protection assay, competition analysis with phosphotyrosine-containing synthetic peptides, and epidermal growth factor receptor (EGFR) mutants to determine the binding sites of the PI domain of Shc on the EGFR. We demonstrate that the PI domain of Shc binds the LXNPXpY motif that encompasses Y-1148 of the activated EGFR. We conclude that the PI domain imparts to Shc its ability to bind the NPXpY motif.

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Citations

Sep 21, 2002·Microscopy Research and Technique·Claudia WellbrockManfred Schartl
Jul 9, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Guiying LiTong Wu
Sep 1, 1996·The Journal of Laboratory and Clinical Medicine·B Margolis
Jun 5, 2002·Annual Review of Biochemistry·Joachim Herz, Hans H Bock
Jun 12, 2012·Metabolism: Clinical and Experimental·Kevork HagopianJon J Ramsey
Jan 15, 2013·Trends in Biochemical Sciences·Lauren E Locascio, Daniel J Donoghue
Aug 16, 2011·FEBS Letters·Mikaël FeracciFrançoise Guerlesquin
Jan 20, 1999·Proceedings of the National Academy of Sciences of the United States of America·U GaykoN Perrimon
Sep 12, 2012·Molecular & Cellular Proteomics : MCP·Hannah JohnsonForest M White
Mar 26, 1999·European Journal of Biochemistry·C Wellbrock, M Schartl
Sep 14, 2012·The Biochemical Journal·Melanie K B Wills, Nina Jones
Feb 11, 2000·Radiation Research·R K Schmidt-UllrichK Valerie
May 31, 1996·The Journal of Biological Chemistry·E D FixmanM Park

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