R-Cadherin expression inhibits myogenesis and induces myoblast transformation via Rac1 GTPase.
Cadherins are transmembrane glycoproteins that mediate Ca(2+)-dependent homophilic cell-cell adhesion and play a crucial role in proliferation, differentiation, and cell transformation. The goal of this study was to understand why R-cadherin is found in rhabdomyosarcomas (RMS), tumors of skeletal muscle origin, whereas it is absent in normal myoblasts. We show that R-cadherin expression in C2C12 myoblasts causes inhibition of myogenesis induction and impairment of cell cycle exit when cells are cultured in differentiation medium. Furthermore, R-cadherin expression elicits myoblast transformation, as shown by anchorage-independent growth in soft agar in vivo tumor formation assays and increased cell motility. In contrast, inhibition of R-cadherin expression using RNA interference hinders growth of RD cell line in soft agar and its tumorigenicity in mice. The analysis of the nature of R-cadherin-mediated signals shows that R-cadherin-dependent adhesion increases Rac1 activity. Dominant-negative forms of Rac1 inhibit R-cadherin-mediated signaling and transformation. In addition, expression of R-cadherin results in perturbed function of endogenous N-cadherin and M-cadherin. Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.
Kucharczak
Jérôme
J
CRBM, Université Montpellier 2 et 1, Centre National de la Recherche Scientifique UMR, France.
Charrasse
Sophie
S
Comunale
Franck
F
Zappulla
Jacques
J
Robert
Bruno
B
Teulon-Navarro
Isabelle
I
Pèlegrin
André
A
Gauthier-Rouvière
Cécile
C
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D024510:Muscle Development / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D012208:Rhabdomyosarcoma / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; C083970:R-cadherin; D020830:rac1 GTP-Binding Protein