The Roles of the Protein Tyrosine Phosphatases PTPN3 and PTPN4 in T cellsand PTPN11 in Tissue Remodeling.

[摘要] PTPN3 and PTPN4 are closely-related non-receptor protein tyrosine phosphatases (PTP) that contain FERM and PDZ domains.Both PTP have been implicated as negative-regulators of early signal transduction through the TCR, acting to dephosphorylate the TCRzeta chain.To determine if PTPN3 functions as a physiological negative-regulator of TCR signaling in primary T cells we generated gene-trapped and gene-targeted mouse strains that lack expression of catalytically-active PTPN3.Numbers and ratios of T cells in primary and secondary lymphoid organs and TCR-induced signal transduction, cytokine production, and proliferation were normal in PTPN3-deficient mice.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 PTP that is distantly related to PTPN3 and PTPN4.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.However, triple-mutant T cells are phenotypically indistinguishable from PTPN13 single-deficient T cells. We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction.SHP-2 (PTPN11) is essential for signaling from multiple classes of cell surface receptors.Mice deficient in SHP-2 expression exhibit defective gastrulation and fail to survive, which has precluded the use of non-conditional SHP-2 deficient mice to examine the role of SHP-2 in mature animals.To study this, we have used a conditional SHP-2 deficient mutant together with an ubiquitin promoter-driven ERT2-Cre transgene to mediate drug inducible deletion of SHP-2 in multiple tissues in adult mice.Using this model, we have determined that induced deletion of SHP-2 results in lethality preceded by weight loss.Epidermal acanthosis, anemia and premature thymic involution were also observed in these mice.Roles for SHP-2 in the homeostasis of the skeletal system are further demonstrated by the striking bone and cartilage remodeling defects resulting from the loss of SHP-2 in this model.

[发布机构] University of Michigan

[效力级别] Signal Transduction

[关键词] Immunology;Signal Transduction;Protein Tyrosine Phosphatase;Microbiology and Immunology;Science;Microbiology & Immunology