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© The Rockefeller University Press, 0021-9525/1997//1057 $5.00
The Journal of Cell Biology, Volume 137, Number 5, , 1997 1057-1068

Article

A Natural Hepatocyte Growth Factor/Scatter Factor Autocrine Loop in Myoblast Cells and the Effect of the Constitutive Met Kinase Activation on Myogenic Differentiation



Sergio Anastasi*, Silvia Giordano{ddagger}, Olga Sthandier*, Giovanna Gambarotta{ddagger}, Rossella Maione*, Paolo Comoglio{ddagger}, and Paolo Amati*

* Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università di Roma La Sapienza, 00161 Roma; and {ddagger} Institute for Cancer Research, Università di Torino, Facoltà di Medicina, Torino, Italy

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 (p65tpr-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 p65tpr-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 p65tpr-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.

1. Abbreviations used in this paper: HGF, hepatocyte growth factor; h-HGF/SF, human HGF/SF; h-met, human isoform of met receptor; HS, horse serum; IGF, insulin-like growth factor; LTR, long terminal repeat; MHC, myosin heavy chain; MHCe, embryonic MHC; SF, scatter factor.

Please address all correspondence to Paolo Amati, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università di Roma La Sapienza, Viale Regina Elena 324, 00161 Roma, Italy. Tel.: (39) 6-490393. Fax: (39) 6-4462891. e-mail: amati{at}dbu.uniroma1.it


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