Negative Suppressors of Oncogenic Activation of the Met Receptor Tyrosine Kinase
Abstract
The Hepatocyte Growth Factor (HGF) RTK, Met, regulates cell proliferation, differentiation, migration, invasion and survival. Met activation is tightly controlled through several levels of regulation to achieve an appropriate biological response. In addition to mutations that activate the Met receptor in human cancer, I have previously shown that the specific uncoupling of Met from ubiquitination results in its oncogenic activation through deregulate endocytosis. My recent work has uncovered a novel role for the Gab1 scaffold in regulating Met internalization and subsequent degradation. HGF stimulation induces membrane ruffling events including the formation of lamellipodia and circular dorsal ruffles (CDRs). I show that Gab1 localizes to CDRs and recruits the Met receptor to this plasma membrane compartment where receptors are then internalized into the cell. Overexpression of Gab1 in HeLa and MDCK cells increases CDR formation, induces a more rapid Met translocation to a perinuclear compartment and enhances HGF induced Met degradation. Mutations in Gab1 that impair recruitment to Met or the plasma membrane, fail to enhance Met degradation. Interestingly, we also show that the endocytic protein, STAM2, can associate with Gab1 and is enriched in CDRs with Gab1. This represents a novel function for both proteins in normal Met downregulation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA469550
Entities
People
- Jasmine V. Abella
Organizations
- McGill University