The Met protooncogene encodes a receptor tyrosine kinase that is deregulated by point mutation, and overexpression/amplification in a number of human tumours. The Met receptor is also oncogenically activated following genomic rearrangement which generates a cytoplasmic, constitutively activated fusion protein, Tpr-Met. In addition to autophosphorylation sites within the catalytic domain, the carboxy terminus of Tpr-Met/Met contains a single major site of autophosphorylation, tyrosine 489. This tyrosine residue represents a unique multisubstrate binding site, capable of binding numerous intracellular proteins, and is critical for the biological activities of both the Met receptor and Tpr-Met oncoprotein. Addition of the c-src myristoylation sequence to the amino terminus of the normally cytoplasmic Tpr-Met, localizes Tpr-Met to plasma membranes and enhances cellular transformation, in vitro invasion, and tumourigenicity. Furthermore, a membrane targetted Tpr-Met is localized to a similar subcellular compartment as the Met receptor, and alters the complement of signalling proteins required for efficient transformation. In this respect, a membrane localized Tpr-Met resembles oncogenic forms of the transmembrane Met receptor, and provides a model with which to study transformation by Met receptor oncoproteins. Significantly, membrane localization of Tpr-Met induces a phosphoinositide 3' kinase (PI3' K) dependent autocrine loop, involving the production of hyaluronic acid (HA), and post-translational modification of the cell surface receptor for HA, CD44. PI3'K activity and the HA/CD44 autocrine loop, are dependent on the multisubstrate binding site, tyrosine 489, and tyrosine residue 498, a residue with no previously described biochemical function. Although the exact mechanisms by which PI3'K regulates HA production are unclear, the induction of a HA/CD44 autocrine loop may represent a novel mechanism by which deregulated receptor tyrosine kinases increase their onco
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.37575 |
| Date | January 1999 |
| Creators | Kamikura, Darren M. |
| Contributors | Park, Morag (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 | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001681451, proquestno: NQ55343, Theses scanned by UMI/ProQuest. |
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