A MULTIFUNCTIONAL DOCKING SITE MEDIATES SIGNALING AND TRANSFORMATION BY THE HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR-RECEPTOR FAMILY

Signaling by tyrosine kinase receptors is mediated by selective intera ctions between individual Src homology 2 (SH2) domains of cytoplasmic effecters and specific phosphotyrosine residues in the activated recep tor. Here, we report the existence in the hepatocyte growth factor/sca tter factor (HGF/SF) receptor of a multifunctional docking site made o f the tandemly arranged degenerate sequence YVH/NV. Phosphorylation of this site mediates intermediate- to high-affinity interactions with m ultiple SH2-containing signal transducers, including phosphatidylinosi tol 3-kinase, phospholipase C gamma, pp60(c-src), and the GRB-2-Sos co mplex. Mutation of the two tyrosines results in loss of biological fun ction, as shown by abrogation of the transforming activity in the onco genic counterpart of the receptor. The same bidentate motif is conserv ed in the evolutionarily related receptors Sea and Ron, suggesting tha t in all members of the HGF/SF receptor family, signal transduction is channeled through a multifunctional binding site.