An alternative to phosphotyrosine-containing motifs for binding to an SH2 domain

Biochemical and Biophysical Research Communications
M RojasY Z Lin

Abstract

Shc is an important signalling protein whose overexpression leads to cell transformation in NIH 3T3 fibroblasts. Although the formation of Shc/Grb2 complexes involving Shc tyrosine residue 317 is necessary to induce this transformation, the Shc proteins in these Shc-overexpressing cells are not substantially tyrosine-phosphorylated. This observation led to our hypothesis that the non-phosphorylated Tyr317-containing region of Shc might have specific affinity for the Grb2 protein. We show here that cell-permeable peptides encompassing the Shc Tyr317 region, 312FDD-PSYVNVQNL323, can bind to the SH2 domain of Grb2 regardless of the state of tyrosine phosphorylation. When delivered into cells, both phosphorylated and non-phosphorylated Shc peptides inhibit growth factor-induced Shc/Grb2 protein-protein interaction. The non-phosphorylated Shc peptides with single point mutations at Asp313, Asp314, or Tyr317 are inactive, suggesting that these residues play an important role in Grb2 protein recognition. Our findings represent the first paradigm of the specific interaction between an unphosphorylated tyrosine-containing region and an SH2 domain and have important implications for understanding the mechanism of cell transformation by S...Continue Reading

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Citations

Apr 29, 1998·Nature Biotechnology·M RojasY Z Lin
Jul 30, 2009·Expert Opinion on Drug Delivery·Gene L Bidwell, Drazen Raucher
Feb 1, 2005·Biochimica Et Biophysica Acta·Kazuya Machida, Bruce J Mayer
Nov 20, 1997·The Journal of Biological Chemistry·L OliginoC R King
Jan 9, 2008·Journal of Peptide Science : an Official Publication of the European Peptide Society·Sónia Troeira Henriques, Miguel A R B Castanho
Jun 14, 2005·American Journal of Physiology. Lung Cellular and Molecular Physiology·Ana L MoraMauricio Rojas
Sep 8, 2006·The Biochemical Journal·Sónia Troeira HenriquesMiguel A R B Castanho
Apr 8, 1998·The Journal of Peptide Research : Official Journal of the American Peptide Society·C DuY Z Lin
Jan 15, 1999·Journal of Medicinal Chemistry·Z J YaoT R Burke
Mar 1, 2000·Biochemical and Biophysical Research Communications·I LappalainenM Vihinen
Feb 3, 1998·Biochemical and Biophysical Research Communications·M Vihinen, C I Smith
Oct 18, 2000·Advanced Drug Delivery Reviews·S Dokka, Y Rojanasakul
Feb 26, 2000·Trends in Pharmacological Sciences·M LindgrenU Langel

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