Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase SH-PTP1.

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摘要：

SH-PTP1 (also known as PTP1C, HCP, and SHP) is a non-transmembrane protein tyrosine phosphatase (PTPase) containing two tandem Src homology 2 (SH2) domains. We show here that the two SH2 (N-SH2 and C-SH2) domains in SH-PTP1 have different functions in regulation of the PTPase domain and thereby signal transduction. While the N-terminal SH2 domain is both necessary and sufficient for autoinhibition through an intramolecular association with the PTPase domain, truncation of the C-SH2 domain [SH-PTP1(Δ CSH2) construct] has little effect on SH-PTP1 activity. A synthetic phosphotyrosine residue (pY) peptide derived from the erythropoietin receptor (EpoR pY429) binds to the N-SH2 domain and activates both wild-type SH-PTP1 and SH-PTP1(Δ CSH2) 60- to 80-fold. Another pY peptide corresponding to a phosphorylation site on the IgG Fc receptor (Fcγ RIIB1 pY309) associates with both the C-SH2 domain (Kd = 2.8 μ M) and the N-SH2 domain (Kd = 15.0 μ M) and also activates SH-PTP1 12-fold. By analysis of the effect of the Fcγ RIIB1 pY309 peptide on SH-PTP1(Δ CSH2), SH-PTP1(R30K/R33E), SH-PTP1(R30K/R136K), and SH-PTP1(R136K) mutants in which the function of either the N-or C-SH2 domain has been impaired, we have determined that both synthetic pY peptides stimulate SH-PTP1 by binding to its N-SH2 domain; binding of pY ligand to the C-SH2 domain has no effect on SH-PTP1 activity. We propose that the N-terminal SH2 domain serves both as a regulatory domain and as a recruiting unit, whereas the C-terminal SH2 domain acts merely as a recruiting unit.

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关键词：

Biochemistry

DOI：

10.1073/pnas.93.3.1141

被引量：

305

年份：

1996