In response to extra-cellular cues, cells activate signal transduction pathways to elicit a biological response. Cell surface growth factor receptors such as the Met receptor tyrosine kinase (RTK) activate signals that result in cellular proliferation, survival, migration, as well as epithelial morphogenesis. In order for signal transduction to occur, docking proteins are recruited to the activated RTK, become phosphorylated on tyrosine residues, which then serve as docking sites for the recruitment of other signaling proteins. Docking proteins function to diversify the signal by assembling multi-protein complexes. The Gab1 docking protein is the most tyrosine phosphorylated protein upon Met receptor activation and is required for Met mediated signaling and biology. / Gab1 belongs to a family of docking proteins including the highly related Gab2 protein. Gab1 promotes signals for epithelial morphogenesis downstream of the Met receptor, however Gab2 is unable to do so. Insertion of the Gab1 Met binding Motif (MBM) which confers direct binding to the Met receptor, as well as membrane targeting of Gab2 is sufficient to switch the capacity of Gab2 to activate the morphogenic program, cell scatter and lamellipodia formation. This is achieved via activation of sustained signaling pathways, and redistribution of the Gab protein, and associated molecules to sites of lamellipodia formation at the peripheral edge of the cell. / Activation of the Met RTK, promotes the formation of dorsal ruffles on the apical surface of epithelial cells. The Met receptor, Gab1 and Gab1 associated molecules Shp2, Crk, and p8S subunit of PI3K, are localized to these structures, however only the Gab1erk complex is required to drive dorsal ruffle formation. Gab1 is required for Met induced dorsal ruffles as well as downstream the PDGF and EGF RTKs. These are a signaling micro-environment which results in enhanced receptor degradation. Inhibition or enhancement of Met mediated dorsal ruffle formation correlates with receptor stability. / Dorsal ruffle formation downstream of Met requires the enzymatic activity of PI3K and PLCgamma, both enzymes that metabolize PIP2, and form complexes with Gab1 downstream of Met. PLCgamma and the PIP3 lipid product of PI3K are co-localized with Gab1 in dorsal ruffles. Gab1 engages with elements of the cytoskeleton, actin and cortactin, providing a link between growth factor signaling and remodeling of the actin cytoskeleton. Gab1 is localized to membrane protrusions of the basal surface in organoid cultures and is required for actin protrusions of the basal surface of breast cancer cells.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.115673 |
| Date | January 2008 |
| Creators | Frigault, Melanie M. (Melanie Mae), 1979- |
| 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: 003132479, proquestno: AAINR66293, Theses scanned by UMI/ProQuest. |
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