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.
Highlights
A common event in cellular signal transduction is the phosphorylation of proteins on tyrosine residues which results in diverse cellular outcomes
To examine the extent of differentiation, cells were re-stimulated with CD3 antibody and secretion of IFN-c, IL-4 and IL-17, respectively, was determined by ELISA (Figure 7). Results of these analyses showed that T cells from PTPN3/PTPN4-doubledeficient mice were able to differentiate along the T helper-1 (Th1), T helper-2 (Th2) and Th17 lineages to an extent comparable to that observed with T cells from wild-type mice
The non-receptor protein tyrosine phosphatases (PTP), SHP-1 and PEP, are established physiological negative-regulators of T cell antigen receptor (TCR) signal transduction that act by dephosphorylating protein tyrosine kinases (PTK) that become activated at an early point in the TCR signaling cascade [10,11,12]
Summary
A common event in cellular signal transduction is the phosphorylation of proteins on tyrosine residues which results in diverse cellular outcomes. This phosphorylation is mediated by protein tyrosine kinases (PTK). One of the first events in the well-established TCR signaling cascade is the phosphorylation and activation of the Src-family PTK, LCK and FYN [6]. These PTK phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) present within the cytoplasmic tails of invariant CD3 and TCRf proteins that form part of the TCR complex [7]. These transcription factors drive the expression of new genes that result in cytokine secretion, cytokine receptor expression, cell division, and effector cell differentiation
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