Activation of ZAP-70 through Specific Dephosphorylation at the Inhibitory Tyr-292 by the Low Molecular Weight Phosphotyrosine Phosphatase (LMPTP)

The ZAP-70 protein-tyrosine kinase plays a central role in signaling from the T cell antigen receptor. Recruitment and activation of ZAP-70 are transient and are terminated by phosphorylation of negative regulatory tyrosine residues and dephosphorylation of positively acting sites. We report that th...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-07, Vol.277 (27), p.24220-24224
Main Authors: Bottini, Nunzio, Stefanini, Lavinia, Williams, Scott, Alonso, Andres, Jascur, Thomas, Abraham, Robert T., Couture, Clément, Mustelin, Tomas
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Chlorocebus aethiops
Cloning, Molecular
COS Cells
Enzyme Activation
Humans
Isoenzymes - metabolism
Jurkat Cells
Mutagenesis, Site-Directed
Phosphotyrosine - metabolism
Plasmids
Protein Tyrosine Phosphatases - metabolism
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins
Receptors, Antigen, T-Cell - metabolism
Recombinant Fusion Proteins - metabolism
Transfection
ZAP-70 Protein-Tyrosine Kinase
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Summary:The ZAP-70 protein-tyrosine kinase plays a central role in signaling from the T cell antigen receptor. Recruitment and activation of ZAP-70 are transient and are terminated by phosphorylation of negative regulatory tyrosine residues and dephosphorylation of positively acting sites. We report that the low molecular weight protein-tyrosine phosphatase (LMPTP) specifically dephosphorylates the negative regulatory Tyr-292 of ZAP-70, thereby counteracting inactivation of ZAP-70. Expression of low levels of LMPTP resulted in increased ZAP-70 phosphorylation, presumably at the activating Tyr-493 and other sites, increased kinase activity, and augmented downstream signaling to the mitogen-activated protein kinase pathway. The ZAP-70 Y292F mutant was not affected by LMPTP. Our results indicate that LMPTP, like CD45, dephosphorylates a negative regulatory tyrosine site in a protein-tyrosine kinase and thereby strengthens T cell receptor signaling.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M202885200