The T-cell protein tyrosine phosphatase (TC-PTP) is a widely expressed enzyme found at significantly higher levels in immune cells. To determine the signaling pathways and specific cell types affected by the loss of TC-PTP, TC-PTP gene-targeted animals were generated in our laboratory. TC-PTP -/- null mice have severe defects in hematopoiesis, elevated levels of inflammatory cytokines, and die by five weeks of age. These data indicate that TC-PTP plays an important role in hematopoiesis and immune cell activation. However, the identification of any substrates that could explain the role of TC-PTP these processes was lacking. Therefore, studies leading to the identification of physiological substrates of TC-PTP were undertaken. / Work in this thesis demonstrates that TC-PTP targets two members of the Janus family of tyrosine kinases (JAKs), JAK1 and JAK3. Both these JAK family members bound to TC-PTP in in vivo substrate trapping experiments, and hyperphosphorylation of JAK1 was demonstrated in TC-PTP-/- macrophages after treatment with interferon (IFN)-gamma. TC-PTP -/- null mice also have increased numbers of macrophages in the spleen. Studies demonstrated that TC-PTP targets the receptor for the colony-stimulating factor-1 (CSF-1), the primary growth factor that controls the proliferation, differentiation, and survival of macrophages. TC-PTP-/- macrophages have prolonged activation of Erk after CSF-1 stimulation. The number of CSF-1 dependent colony forming cells (CFU-Cs) is increased in TC-PTP-/- null mice, and TC-PTP-/- null hematopoietic progenitor cells produce more committed mononuclear phagocytic precursors in vitro . These data indicate that the loss of TC-PTP results in increased CSF-1 signaling and increased macrophage differentiation. Therefore, two novel classes of substrates for TC-PTP have been identified---members of the JAK family (JAK1 and JAK3) and the CSF-1R. Both substrates play important roles in hematopoiesis and immune cell activation, and their identification provides insight into the mechanism of TC-PTP function in vivo.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111823 |
| Date | January 2005 |
| Creators | Simoncic, Paul D. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002326008, proquestno: AAINR25256, Theses scanned by UMI/ProQuest. |
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