The protein tyrosine phosphatase PTPN4/PTP-MEG1, an enzyme capable of dephosphorylating the TCR ITAMs and regulating NF-kappaB, is dispensable for T cell development and/or T cell effector functions.
T cell receptor signaling processes are controlled by the integrated actions of families of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPases). Several distinct cytosolic protein tyrosine phosphatases have been described that are able to negatively regulate TCR signaling pathways, including SHP-1, SHP-2, PTPH1, and PEP. Using PTPase substrate-trapping mutants and wild type enzymes, we determined that PTPN4/PTP-MEG1, a PTPH1-family member, could complex and dephosphorylate the ITAMs of the TCR zeta subunit. In addition, the substrate-trapping derivative augmented basal and TCR-induced activation of NF-kappaB in T cells. To characterize the contribution of this PTPase in T cells, we developed PTPN4-deficient mice. T cell development and TCR signaling events were comparable between wild type and PTPN4-deficient animals. The magnitude and duration of TCR-regulated ITAM phosphorylation, as well as overall protein phosphorylation, was unaltered in the absence of PTPN4. Finally, Th1- and Th2-derived cytokines and in vivo immune responses to Listeria monocytogenes were equivalent between wild type and PTPN4-deficient mice. These findings suggest that additional PTPases are involved in controlling ITAM phosphorylations.
Young
Jennifer A
JA
Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
Becker
Amy M
AM
Medeiros
Jennifer J
JJ
Shapiro
Virginia S
VS
Wang
Andrew
A
Farrar
J David
JD
Quill
Timothy A
TA
Hooft van Huijsduijnen
Rob
R
van Oers
Nicolai S C
NS
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D019169:Jurkat Cells; D007668:Kidney / Q000166:cytology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D014162:Transfection
D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; C516658:PTPN4 protein, human; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4