UNCOUPLING OF GRB2 FROM THE MET RECEPTOR IN-VIVO REVEALS COMPLEX ROLES IN MUSCLE DEVELOPMENT

Hepatocyte growth factor (HGF) and its receptor, the Met tyrosine kina se, are determinants of placenta, liver, and muscle development. Here, we show that Met function in vivo requires signaling via two carboxyt erminal tyrosines. Mutation of both residues in the mouse genome cause d embryonal death, with placenta, liver, and limb muscle defects, mimi cking the phenotype of met null mutants. In contrast, disrupting the c onsensus for Grb2 binding allowed development to proceed to term witho ut affecting placenta and liver but caused a striking reduction in lim b muscle coupled to a generalized deficit of secondary fibers. These d ata show that the requirements for Met signaling vary depending on the tissue and reveal a novel role for HGF/Met in late myogenesis.