BACKGROUND: The immune response is regulated through a tightly controlled cytokine network. The counteracting balance between protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) activity regulates intracellular signaling in the immune system initiated by these extracellular polypeptides. Mice deficient for the T cell protein tyrosine phosphatase (TCPTP) display gross defects in the hematopoietic compartment, indicating a critical role for TCPTP in the regulation of immune homeostasis. To date, the molecular basis underlying this phenotype has not been reported. RESULTS: We have identified two members of the Janus family of tyrosine kinases (JAKs), JAK1 and JAK3, as bona fide substrates of TCPTP. Inherent substrate specificity in the TCPTP-JAK interaction is demonstrated by the inability of other closely related PTP family members to form an in vivo interaction with the JAKs in hematopoietic cells. In keeping with a negative regulatory role for TCPTP in cytokine signaling, expression of TCPTP in T cells abrogated phosphorylation of STAT5 following interleukin (IL)-2 stimulation. TCPTP-deficient lymphocytes treated with IL-2 had increased levels of tyrosine-phosphorylated STAT5, and thymocytes treated with interferon (IFN)-alpha or IFN-gamma had increased tyrosine-phosphorylated STAT1. Hyperphosphorylation of JAK1 and elevated expression of iNOS was observed in IFN-gamma-treated, TCPTP-deficient, bone marrow-derived macrophages. CONCLUSIONS: We have identified JAK1 and JAK3 as physiological substrates of TCPTP. These results indicate a negative regulatory role for TCPTP in cytokine signaling and provide insight into the molecular defect underlying the phenotype of TCPTP-deficient animals.
BACKGROUND: The immune response is regulated through a tightly controlled cytokine network. The counteracting balance between protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) activity regulates intracellular signaling in the immune system initiated by these extracellular polypeptides. Mice deficient for the T cell protein tyrosine phosphatase (TCPTP) display gross defects in the hematopoietic compartment, indicating a critical role for TCPTP in the regulation of immune homeostasis. To date, the molecular basis underlying this phenotype has not been reported. RESULTS: We have identified two members of the Janus family of tyrosine kinases (JAKs), JAK1 and JAK3, as bona fide substrates of TCPTP. Inherent substrate specificity in the TCPTP-JAK interaction is demonstrated by the inability of other closely related PTP family members to form an in vivo interaction with the JAKs in hematopoietic cells. In keeping with a negative regulatory role for TCPTP in cytokine signaling, expression of TCPTP in T cells abrogated phosphorylation of STAT5 following interleukin (IL)-2 stimulation. TCPTP-deficient lymphocytes treated with IL-2 had increased levels of tyrosine-phosphorylated STAT5, and thymocytes treated with interferon (IFN)-alpha or IFN-gamma had increased tyrosine-phosphorylated STAT1. Hyperphosphorylation of JAK1 and elevated expression of iNOS was observed in IFN-gamma-treated, TCPTP-deficient, bone marrow-derived macrophages. CONCLUSIONS: We have identified JAK1 and JAK3 as physiological substrates of TCPTP. These results indicate a negative regulatory role for TCPTP in cytokine signaling and provide insight into the molecular defect underlying the phenotype of TCPTP-deficient animals.
Authors: Camilla Persson; Catrine Sävenhed; Annie Bourdeau; Michel L Tremblay; Boyka Markova; Frank D Böhmer; Fawaz G Haj; Benjamin G Neel; Ari Elson; Carl-Henrik Heldin; Lars Rönnstrand; Arne Ostman; Carina Hellberg Journal: Mol Cell Biol Date: 2004-03 Impact factor: 4.272
Authors: K Loh; T L Merry; S Galic; B J Wu; M J Watt; S Zhang; Z-Y Zhang; B G Neel; T Tiganis Journal: Diabetologia Date: 2011-11-29 Impact factor: 10.122
Authors: Kim Loh; Atsushi Fukushima; Xinmei Zhang; Sandra Galic; Dana Briggs; Pablo J Enriori; Stephanie Simonds; Florian Wiede; Alexander Reichenbach; Christine Hauser; Natalie A Sims; Kendra K Bence; Sheng Zhang; Zhong-Yin Zhang; Barbara B Kahn; Benjamin G Neel; Zane B Andrews; Michael A Cowley; Tony Tiganis Journal: Cell Metab Date: 2011-10-13 Impact factor: 27.287
Authors: Veena Sangwan; Grigorios N Paliouras; Jasmine V Abella; Nadia Dubé; Anie Monast; Michel L Tremblay; Morag Park Journal: J Biol Chem Date: 2008-09-26 Impact factor: 5.157