Bardelli, Alberto; (1996) Identification of the transduction pathways mediating the cellular responses to the Hepatocyte growth factor/scatter factor. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Hepatocyte Growth Factor (HGF) is a mesenchymal cytokine capable of inducing proliferation and motility (scattering) in epithelial cells. This dual biological response depends on the interaction of HGF with its receptor, the tyrosine kinase c-Met. Ligand-induced activation of the HGF receptor triggers a number of signaling pathways in target cells. Signaling by tyrosine kinase receptors is normally mediated by selective interaction between effectors containing src homology 2 (SH2) domains and specific phosphotyrosine residues in the activated receptor. The HGF receptor is characterized by a unique signal transduction mechanism involving a multi-functional docking site made of two tandemly arranged phosphotyrosines embedded in the degenerate sequence YVH/NV. Upon autophosphorylation, these tyrosines bind and concomitantly activate multiple SH2-containing transducers, including the Grb2/SOS complex, phosphatidylinositol 3-kinase (PI 3-kinase), phospholipase C-γ (PLC-γ) and pp60Src. These interactions are characterized by fast association and dissociation rates thus favoring a rapid exchange of effectors in vivo. The multi-functional docking site is strictly required for the receptor's transforming, scattering, invasive and metastatic ability. Signalling mutants of the multifunctional docking site indicate that preferential coupling of the receptor to either Ras or PI 3-kinase is sufficient to promote scattering, but impairs invasion and metastases. Conversely, concomitant activation of both pathways promotes transformation and invasion, and induces a fully metastatic phenotype. These results imply that HGF receptor-mediated motility, transformation, and invasion have distinct signalling requirements, and suggest that simultaneous activation of Ras and PI-3K is both necessary and sufficient for the HGF receptor invasive-metastatic potential. Altogether these data indicate that the multifunctional docking site represents the main transductional switch for the HGF receptor.

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