Negative regulation of antigen and cytokine-induced intracellular signalling pathways involves several mechanisms including anergy, receptor internalization, recruitment of protein phosphatases, etc. In certain cases, these inhibitory signals specifically target the Src and Jak families of protein tyrosine kinases. Recent work in the laboratory has shown that protein tyrosine kinase Csk and protein tyrosine phosphatase PEP form a complex that inactivates Src kinases in the context of antigen receptor signalling. In this manuscript, I demonstrate that this interaction depends on the SH3 domain of Csk and a typical SH3 domain-binding motif (PXXPXR) present within PEP. Moreover, I show that the Csk SH3 domain recognizes sequences flanking the proline-rich core for in vitro and in vivo binding. In a very different mechanism, negative regulation of Jaks seems to depend, at least in part, on a recently cloned SH2 domain-containing adapter protein, termed suppressor of cytokine signalling-1 (SOCS-1). Recent evidence suggests that the inhibitory effect of SOCS-1 on Jak catalytic activity is tightly regulated by transcriptional and post-translational mechanisms. In this report, I propose an additional regulatory mechanism in the form of translational control. I show that SOCS-1 protein levels are strongly repressed by its GC-rich 5' untranslated region. The implications of these results will be discussed.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.29897 |
| Date | January 1999 |
| Creators | Gregorieff, Alexander. |
| Contributors | Veillette, Andre (advisor) |
| 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 | Master of Science (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001681973, proquestno: MQ55063, Theses scanned by UMI/ProQuest. |
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