ONCOGENIC ACTIVATION OF THE MET RECEPTOR Tyrosine Kinase PRINCIPAL INVESTIGATOR:

How signalling and biological response to the hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK), Met, are coupled to Met trafficking is largely unknown. The Gab1 scaffold protein modulates Met signals involved in cell dispersal and morphogenesis. We show that Gab1 is indispensable for a form of RTK-induced actin remodelling, called dorsal ruffles, in response to HGF, epidermal and platelet derived growth factors. Localisation of Gab1 and activated Met to dorsal ruffles is accompanied by signalling proteins recruited to Gab1. Structure-function demonstrates a requirement for Gab1-Crk complexes for dorsal ruffle formation. Gab1 induced dorsal ruffles promote a polarised signalling microenvironment from which Met is bulk internalised and degraded. Ablation of dorsal ruffles delays Met degradation but diminishes biological responses. We demonstrate an essential role for Gab1 in dorsal ruffle formation by multiple RTKs and provide direct evidence that dorsal ruffles act as a biologically relevant signalling microenvironment and mechanism for receptor down-regulation.