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 kinase, are determinants of placenta, liver, and muscle development. Here, we show that Met function in vivo requires signaling via two carboxy-terminal tyrosines. Mutation of both residues in the mouse genome caused embryonal death, with placenta, liver, and limb muscle defects, mimicking the phenotype of met null mutants. In contrast, disrupting the consensus for Grb2 binding allowed development to proceed to term without affecting placenta and liver but caused a striking reduction in limb muscle coupled to a generalized deficit of secondary fibers. These data show that the requirements for Met signaling vary depending on the tissue and reveal a novel role for HGF/ Met in late myogenesis.
European Molecular Biology Laboratory, Heidelberg, Federal Republic of Germany.
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D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018076:DNA, Complementary / Q000235:genetics; D051380:GRB2 Adaptor Protein; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009024:Morphogenesis; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000196:embryology*; D016254:Mutagenesis, Insertional; D010641:Phenotype; D010920:Placenta / Q000378:metabolism; D011506:Proteins / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D046911:Macromolecular Substances; D011506:Proteins; D011993:Recombinant Fusion Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases