| Activation of the Met receptor tyrosine kinase by its ligand, Hepatocyte Growth Factor (HGF), leads to mitogenesis, cell motility, morphogenesis, and angiogenesis. Mutational analysis has demonstrated the requirement of a single tyrosine within the carboxy-terminus (Y1356) of the Met receptor for the recruitment and activation of all Met-dependent signalling pathways and for the transformation of fibroblasts by the Tpr-Met oncogene. The selective abolishment of Grb2 from the Tpr-Met oncoprotein, by generating an asparagine to histidine mutation two amino acids downstream from Y1356 (N1358H), led to a reduction in Tpr-Met-mediated transformation of fibroblasts. Moreover, Met receptor studies demonstrate that while a Grb2 binding site is not required for epithelial cell motility, it is critical for the formation of branching tubules when cells are suspended in a collagen matrix. This suggests that Grb2-dependent pathways are involved in the organization and polarization of epithelial cells following Met receptor stimulation.; Grb2 associated molecules, Gab1 and Cbl, are highly phosphorylated following stimulation of the Met receptor. Moreover, signaling pathways associated with Gab1 are critical for branching tubulogenesis in epithelial cells.{09}Expression of a constitutively active version of Cbl, 70z-Cbl, results in an epithelial-mesenchymal transition, leading to the breakdown of cellular junctions and reorganization of the actin cytoskeleton. The amino-terminal SH2 domain is the minimal region required to induce morphological changes, which may be mediated through its interaction with the Met receptor, and/or an unidentified protein of 150 kDa. |
