The FERM and PDZ Domain-Containing Protein Tyrosine Phosphatases, PTPN4 and PTPN3, Are Both Dispensable for T Cell Receptor Signal Transduction

Abstract

PTPN3 and PTPN4 are two closely-related non-receptor protein tyrosine phosphatases (PTP) that, in addition to a PTP domain, contain FERM (Band 4.1, Ezrin, Radixin, and Moesin) and PDZ (PSD-95, Dlg, ZO-1) domains. Both PTP have been implicated as negative-regulators of early signal transduction through the T cell antigen receptor (TCR), acting to dephosphorylate the TCRζ chain, a component of the TCR complex. Previously, we reported upon the production and characterization of PTPN3-deficient mice which show normal TCR signal transduction and T cell function. To address if the lack of a T cell phenotype in PTPN3-deficient mice can be explained by functional redundancy of PTPN3 with PTPN4, we generated PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. As in PTPN3 mutants, T cell development and homeostasis and TCR-induced cytokine synthesis and proliferation were found to be normal in PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. PTPN13 is another FERM and PDZ domain-containing non-receptor PTP that is distantly-related to PTPN3 and PTPN4 and which has been shown to function as a negative-regulator of T helper-1 (Th1) and Th2 differentiation. Therefore, to determine if PTPN13 might compensate for the loss of PTPN3 and PTPN4 in T cells, we generated mice that lack functional forms of all three PTP. T cells from triple-mutant mice developed normally and showed normal cytokine secretion and proliferative responses to TCR stimulation. Furthermore, T cell differentiation along the Th1, Th2 and Th17 lineages was largely unaffected in triple-mutants. We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction.

PTPN 3 acts as a tumor suppressor and boosts TGF ‐β signaling independent of its phosphatase activity

“…Among PTPs, PTPN3 is an understudied protein tyrosine phosphatase with very limited implications on its functions. Most studies focus on identification and characterization of PTPN3 substrates such as EGFR, Egs15, and TCRζ (Sozio et al , ; Bauler et al , ; Chen et al , ; Parker, ). PTPN3 has also been reported to interact with vitamin D receptor (VDR), stabilizes VDR in the cytoplasm, and consequently promotes breast cancer growth (Zhi et al , ).…”

The Ras GTPase-activating protein neurofibromin 1 promotes the positive selection of thymocytes

“…T cell polarization was performed as described (Bauler et al, 2008). Briefly, CD44 − , CD4 + T cells from non-TCR Tg mice were stimulated with CD3 and CD28 mAb in complete medium with IL-2 (100 ng/ml) as indicated in Western blotting.…”

A Drosophila‐centric view of protein tyrosine phosphatases

“…Ptpmeg is involved in neuronal circuit formation in the central brain of the fly, regulating both the establishment and stabilization of axonal projection patterns, and its vertebrate orthologs ( PTPN3 and PTPN4 ) are expressed in the nervous system too [110]. The human orthologs of Ptpmeg ( PTPN3 and PTPN4 ) are also negative regulators of T‐cell receptor (TCR) signaling (a function absent in the fly), both dephosphorylating the TCRζ chain [111]. Additionally, PTPN4 is anti‐apoptotic, as was shown by its promotion of the survival of glioblastoma cells, and has been proposed as a therapeutic target [112].…”