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J. Biol. Chem., Vol. 278, Issue 7, 4668-4674, February 14, 2003
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From the Department of Pharmacology and Molecular Sciences, Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205
The protein-tyrosine phosphatase SHP-1 plays a
variety of roles in the "negative" regulation of cell signaling.
The molecular basis for the regulation of SHP-1 is incompletely
understood. Whereas SHP-1 has previously been shown to be
phosphorylated on two tail tyrosine residues (Tyr536
and Tyr564) by several protein-tyrosine kinases, the
effects of these phosphorylation events have been difficult to address
because of the intrinsic instability of the linkages within a
protein-tyrosine phosphatase. Using expressed protein ligation, we have
generated semisynthetic SHP-1 proteins containing phosphotyrosine
mimetics at the Tyr536 and Tyr564 sites. Two
phosphonate analogues were installed, phosphonomethylenephenylalanine (Pmp) and difluorophosphonomethylenephenylalanine (F2Pmp).
Incorporation of Pmp at the 536 site led to 4-fold stimulation of the
SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect. Incorporation of F2Pmp at the 536 site led to 8-fold stimulation of the SHP-1 tyrosine phosphatase
activity and 1.6-fold at the 564 site. A combination of size exclusion chromatography, phosphotyrosine peptide stimulation studies, and site-directed mutagenesis led to the structural model in which tyrosine
phosphorylation at the 536 site engages the N-Src homology 2 domain in an intramolecular fashion relieving basal inhibition. In
contrast, tyrosine phosphorylation at the 564 site has the potential to
engage the C-Src homology 2 domain intramolecularly, which can modestly
and indirectly influence catalytic activity. The finding that
phosphonate modification at each of the 536 and 564 sites can promote
interaction with the Grb2 adaptor protein indicates that the
intramolecular interactions fostered by post-translational modifications of tyrosine are not energetically strong and susceptible to intermolecular competition.
To whom correspondence should be addressed. Tel.: 410-614-0540;
Fax: 410-614-7717; E-mail: pcole@jhmi.edu.
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