The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein

The receptor of Hepatocyte Growth Factor-Scatter Factor (HGF) is a tyrosine kinase which regulates cell motility and growth. After ligand-induced tyrosine phosphorylation, the HGF receptor associates with the Shc adaptor, via the SH2 domain. Site-directed mutagenesis of the HGF receptor indicates that phosphotyrosines Y¹³⁴⁹VHV and Y¹³⁵⁶VNV can work as docking sites for Shc. The K(d) of this interaction, measured in real time using synthetic phosphopeptides and recombinant Shc on a BIAcore biosensor, is 150 nm for both sites. After stimulation of the HGF receptor, Shc is phosphorylated on Y³¹⁷VNV, generating an high affinity binding site for Grb2 (K(d) = 15 nM). This duplicates the high affinity binding site for Grb2 present on the HGF receptor (Y¹³⁵⁶VNV). Thus HGF stimulation can trigger the Ras pathway by recruiting Grb2 both directly through the receptor, and indirectly, through Shc. Overexpression of wild-type Shc, but not of the Y³¹⁷→F mutant, enhances cell migration and growth in response to HGF. These data show that Shc is a relevant substrate of the HGF receptor, and works as an 'amplifier' of the motogenic as well as of the mitogenic response.