Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP.
The proline-, glutamic acid-, serine- and threonine-enriched protein tyrosine phosphatase PEP, which is expressed primarily in hematopoietic cells, was recently discovered to be physically associated with the 50-kDa cytosolic protein tyrosine kinase (PTK) Csk, an important suppressor of Src family PTK, including Lck and Fyn in T cells. We report that this phosphatase has an inhibitory effect on TCR-induced transcriptional activation of the c-fos proto-oncogene and elements from the IL-2 gene promoter. Catalytically inactive mutants of PEP had no effects in these assays. Expression of PEP also reduced activation of the N-terminal c-Jun kinase Jnk2 in response to receptor ligation, but not in response to UV light. In agreement with a more receptor-proximal site of action, we found that PEP reduced the TCR-induced increase in tyrosine phosphorylation of an Lck mutant, Lck-Y505F, which is only phosphorylated on tyrosine 394, the positive regulatory site. Finally, we observed that PEP reduced c-fos activation in a synergistic manner with Csk, supporting the notion that these two enzymes form a functional team acting on Src family kinases involved in TCR signaling.
Gjörloff-Wingren
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A
Laboratory of Signal Transduction, Sidney Kimmel Cancer Center, San Diego, USA.
Saxena
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Williams
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S
Hammi
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D
Mustelin
T
T
D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*; D000090063:Proto-Oncogene Mas; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011948:Receptors, Antigen, T-Cell; C516738:PTPN12 protein, human; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases