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The roles of Src homology 3 (SH3) domains of growth factor receptor bound protein 2 (Grb2) in downstream pathways, elicited by hepatocyte growth factor (HGF).

Adamopoulos, I.E.; (2005) The roles of Src homology 3 (SH3) domains of growth factor receptor bound protein 2 (Grb2) in downstream pathways, elicited by hepatocyte growth factor (HGF). Masters thesis , University of London. Green open access

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Abstract

It is known that functional binding sites in the carboxyl-terminus of the hepatocyte growth factor (HGF) receptor, c-Met, are required to bind growth factor receptor bound protein 2 (Grb2) and transduce the motility and proliferation response to HGF. Downstream targets coupled to the Src homology 3 (SH3) domains of Grb2 following HGF stimulation are only partly known. A recent finding that approximately 50% of the endogenous Grb2 is localised within the detergent-insoluble (cytoskeletal) fraction of A431 epidermoid carcinoma cells, implied that Grb2 may link receptor tyrosine kinase signals to the cytoskeleton. Therefore Grb2 may be involved in cytoskeletal rearrangement during cell motility and invasion. The significance of Grb2 SH3 domains in driving the cellular phenotype in response to HGF was investigated in cell lines expressing the HGF receptor and transfected with wild-type and dominant-negative constructs lacking the Grb2 SH3 domains. High apoptotic rates of cell transfections have implied that the SH3 domains of Grb2 are able to sequester phosphoinositide kinases (PI3-Kinase), which is also responsible for cell motility downstream of Met, presumably through formation of a protein multicomplex, and therefore inactivate or partly inhibit the protein kinase B (PKB)/Akt survival pathway. Recent evidence suggests Grb2 involvment in survival pathways by formation of protein multicomplexes. Therefore the involvment of Grb2 in a survival pathway through sequestering of PI3-Kinase or Cbl-PI3-Kinase from a Src/Cbl/PI3-Kinase complex able to activate PKB/Akt is hypothesized and discussed.

Type: Thesis (Masters)
Title: The roles of Src homology 3 (SH3) domains of growth factor receptor bound protein 2 (Grb2) in downstream pathways, elicited by hepatocyte growth factor (HGF).
Identifier: PQ ETD:594381
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by Proquest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1446411
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