The Role of the PTPH1-Family of Protein Tyrosine Phosphatases In T Cells



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The alpha beta T cell receptor complex activates intracellular signaling cascades by coupling to several families of protein tyrosine kinases and protein tyrosine phosphatases. Following T cell receptor interactions with cognate peptide/major histocompatibility complexes, Src-family protein tyrosine kinases phosphorylate two tyrosine residues in a conserved amino acid motif termed the immunoreceptor tyrosine-based activation motif. The immunoreceptor tyrosine-based activation motifs are present in one or more copies in the cytoplasmic tails of the T cell receptor invariant chains, CD3 gamma, delta, epsilon and zeta. In all T cell receptor signaling events, the immunoreceptor tyrosine-based activation motifs are transiently phosphorylated. We used a large-scale screen to identify protein tyrosine phosphatase candidates dephosphorylating the T cell receptor zeta immunoreceptor tyrosine-based activation motifs. PTPH1 was identified in this screen, but its endogenous expression was difficult to detect in T cells. Based on sequence homology, PTPN4 was also considered as a putative regulator of phospho-zeta. T cell receptor zeta was bound and dephosphorylated by PTPN4. Overexpression of wild-type PTPN4 inhibited T cell receptor-induced AP-1 and NFkappaB activation in T cells. The overexpression of a substrate-trapping derivative of PTPN4 significantly augmented NFkappaB activation. This finding demonstrates a role for PTPN4 in the regulation of the NFkappaB pathway. PTPN4 knock-out mice were generated to assess the role of this PTPase in lymphocytes. This is the first description of a PTPN4-deficient animal model. No major developmental defects were observed in the PTPN4 knock-out mice. However, PTPN4-deficient animals had altered peripheral effector/memory T cell populations. While early T cell activation and T cell receptor-induced signal transduction events were normal, peripheral T cells from PTPN4-null mice secreted elevated levels of IL-4, IL-5, and IL-13 in the absence of PTPN4. This suggests that PTPN4 has a selective role in regulating effector T cell differentiation. Taken together, both PTPH1 and PTPN4 may regulate T cell receptor zeta phosphorylation, but the unique functions of these two protein tyrosine phosphatases indicate non-overlapping substrates.

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Receptors, Antigen, T-Cell, T-Lymphocytes, Protein Tyrosine Phosphatase, Non-Receptor Type 4


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