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 signaling, internalization and subsequent degradation. HGF stimulation induces membrane ruffling events required to initiate cell migration including the formation of lamellipodia and dorsal ruffles (DRs). I show that Gab1 localizes to and is required for DR formation and recruits the Met receptor to this plasma membrane compartment where receptors and various Gab1 binding signaling molecules become concentrated. Disruption of this signaling DR compartment severely alters Met dependent MAPK signaling profile and blocks cell migration. Paradoxically the Met receptor is also more efficiently internalized and subsequently degraded through DR and disruption of DR drastically delays Met degradation. This underscores the importance of understating RTK subcellular localization in addition to receptor stability and how this provides a further level of regulation on biological outcome. Interestingly, we also show that the endocytic protein, STAM2, can associate with Gab1 and is enriched in DRs with Gab1. This represents a novel function for both proteins in normal Met downregulation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2008
- Accession Number
- ADA504730
Entities
People
- Jasmine V. Abella
Organizations
- McGill University