HGF controls branched morphogenesis in tubular glands

The c-MET gene encodes the tyrosine kinase p190(MET), the receptor for a molecule known as Scutter Factor (SF) or Hepatocyte Growth Factor (HGF). This molecule has biological activities on epithelial sheets, including mitogenesis, cell-cell dissociation, stimulation of migration into the extracellular matrix, induction of cell polarization and branched tubulogenesis. The p190(MET) receptor is a heterodimer of two (alpha beta) disulfide-linked protein subunits. The RON and SEA genes encode tyrosine kinases that are structurally homologous to the HGF receptor. The three members of MET family elicit the same array of unusual biological responses that include "scattering", growth, and induction of polarized tubular structures. Recently, we identified another family of genes (SEX genes) encoding putative receptors with structural similarities to the extracellular domain of the HGF receptor and large cytoplasmic domains with unknown functions. Receptor autophosphorylation triggers the signal transduction pathways inside the target cells. The phosphorylation of an intracellular site made of a specific two-tyrosine containing sequence, mediates interactions with multiple SH2-containing intracellular signaling molecules. The multifunctional docking site is conserved and functional in the receptors encoded by RON and SEA. Substitution of N-1358, critical for recruiting the Grb2/SoS complex and activating the Ras pathway, results in the abrogation of the growth response, while mutation of H-1351 into N, generating a docking site inefficient to activate the PI3-kinase pathway, stimulates growth but fails to support the induction of scattering and branched tubulogenesis. Activation of a third pathway, mediated by direct phosphorylation on tyrosine of STAT-3 plays a critical role in induction of cell polarization and formation of tubular structures.