Protein tyrosine phosphatases PTP-1B and TC-PTP play nonredundant roles in macrophage development and IFN-γ signaling

摘要

The control of tyrosine phosphorylation depends on the fine balance between kinase and phosphatase activities. Protein tyrosine phosphatase 1B (PTP-1B) and T cell protein tyrosine phosphatase (TC-PTP) are 2 closely related phosphatases known to control cytokine signaling. We studied the functional redundancy of PTP-1B and TC-PTP by deleting 1 or both copies of these genes by interbreeding TC-PTP and PTP-1 B parental lines. Our results indicate that the double mutant {tcptp~(-/1-)ptp~1 b~(-/-)) is lethal at day E9.5-10.5 of embryonic development with constitutive phosphorylation of Stat1. Mice heterozygous for TC-PTP on a PTP-1 B-deficient background (tcptp~(+/-)ptp1b~(-/-)) developed signs of inflammation. Macrophages from these animals were- highly sensitive to IFN-y, as demonstrated by increased Stati phosphorylation and nitric oxide production. In addition, splenic T cells demonstrated increased IFN-y secretion capacity. Mice with deletions of single copies of TC-PTP and PTP-1 B {tcptp~(+/-)ptp1b~(+/-)) exhibited normal development, confirming that these genes are not interchangeable. Together, these data indicate a nonredundant role for PTP-1 B and TC-PTP in the regulation of IFN signaling.