A natural hepatocyte growth factor/scatter factor autocrine loop in myoblast cells and the effect of the constitutive Met kinase activation on myogenic differentiation

J Cell Biol. 1997 Jun 2;137(5):1057-68. doi: 10.1083/jcb.137.5.1057.


As a rule, hepatocyte growth factor/scatter factor (HGF/SF) is produced by mesenchymal cells, while its receptor, the tyrosine kinase encoded by the met proto-oncogene, is expressed by the neighboring epithelial cells in a canonical paracrine fashion. In the present work we show that both HGF/SF and met are coexpressed by undifferentiated C2 mouse myoblasts. In growing cells, the autocrine loop is active as the receptor exhibits a constitutive phosphorylation on tyrosine that can be abrogated by exogenously added anti-HGF/SF neutralizing antibodies. The transcription of HGF/SF and met genes is downregulated when myoblasts stop proliferating and differentiate. The coexpression of HGF/SF and met genes is not exclusive to C2 cells since it has been assessed also in other myogenic cell lines and in mouse primary satellite cells, suggesting that HGF/SF could play a role in muscle development through an autocrine way. To analyze the biological effects of HGF/SF receptor activation, we stably expressed the constitutively activated receptor catalytic domain (p65(tpr-met)) in C2 cells. This active kinase determined profound changes in cell shape and inhibited myogenesis at both morphological and biochemical levels. Notably, a complete absence of muscle regulatory markers such as MyoD and myogenin was observed in p65(tpr-met) highly expressing C2 clones. We also studied the effects of the ectopic expression of human isoforms of met receptor (h-met) and of HGF/SF (h-HGF/SF) in stable transfected C2 cells. Single constitutive expression of h-met or h-HGF/SF does not alter substantially the growth and differentiation properties of the myoblast cells, probably because of a species-specific ligand-receptor interaction. A C2 clone expressing simultaneously both h-met and h-HGF/SF is able to grow in soft agar and shows a decrease in myogenic potential comparable to that promoted by p65(tpr-met) kinase. These data indicate that a met kinase signal released from differentiation-dependent control provides a negative stimulus for the onset of myogenic differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Dogs
  • Down-Regulation / physiology
  • Enzyme Activation
  • Gene Expression / physiology
  • Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Kidney Tubules, Distal / cytology
  • Liver / cytology
  • Mice
  • Mice, Inbred C3H
  • Muscles / chemistry
  • Muscles / cytology*
  • Muscles / enzymology
  • MyoD Protein / genetics
  • MyoD Protein / metabolism
  • Myogenin / genetics
  • Myogenin / metabolism
  • Phosphotransferases / metabolism*
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-met
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Species Specificity
  • Teratocarcinoma
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology


  • MAS1 protein, human
  • MYOG protein, human
  • MyoD Protein
  • Myog protein, mouse
  • Myogenin
  • Proto-Oncogene Mas
  • RNA, Messenger
  • Recombinant Proteins
  • Hepatocyte Growth Factor
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Phosphotransferases
  • Proto-Oncogene Proteins c-met
  • Receptor Protein-Tyrosine Kinases