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A more recent version of this article appeared on March 19, 2004
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Papers In Press, published online ahead of print December 29, 2003
J. Biol. Chem, 10.1074/jbc.M309096200
Submitted on August 18, 2003
Revised on December 15, 2003
Accepted on December 23, 2003

Effective dephosphorylation of Src substrates by SHP-1

Carsten Frank, Carmen Burkhardt, Diana Imhof, Jens Ringel, Olaf Zschörnig, Karin Wieligmann, Martin Zacharias, and Frank D. Böhmer

Department of Molecular Cell Biology, Jena University Hospital, Jena, Jena D-07747

Corresponding Author: i5frbo{at}rz.uni-jena.de

The protein-tyrosine phosphatase SHP-1 is a negative regulator of multiple signal transduction pathways. We observed that SHP-1 effectively antagonized Src-dependent phosphorylations in HEK293 cells. This occured by dephosphorylation of Src substrates, since Src activity was unaffected in the presence of SHP-1. One reason for efficient dephosphorylation was activation of SHP-1 by Src. Recombinant SHP-1 had elevated activity subsequent to phosphorylation by Src in vitro, and SHP-1 variants with mutated phosphorylation sites in the C-terminus, SHP-1 Y538F, and SHP-1 Y538, 566F were less active toward Src-generated phosphoproteins in intact cells. A second reason for efficient dephosphorylation is the substrate selectivity of SHP-1. Pulldown experiments with different GST-SHP-1 fusion proteins revealed efficient interaction of Src-generated phosphoproteins with the SHP-1 catalytic domain rather than with the SH2 domains. Phosphopeptides which correspond to good Src substrates were efficiently dephosphorylated by SHP-1 in vitro. Phosphorylated 'optimal Src substrate' AEEEIpYGEFEA and a phosphopeptide corresponding to a recently identified Src phosphorylation site in p120 catenin, DDLDpY296 GMMSD, were excellent SHP-1 substrates. Docking of these phosphopeptides into the catalytic domain of SHP-1 by molecular modeling was consistent with the biochemical data and explains the efficient interaction. Acidic residues N-terminal of the phosphotyrosine seem to be of major importance for efficient substrate interaction. Residues C-terminal of the phosphotyrosine probably contribute to the substrate selectivity of SHP-1. We propose that activation of SHP-1 by Src and complementary substrate specificities of SHP-1 and Src may lead to very transient Src signals in the presence of SHP-1


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