BETA-D-1 INTEGRIN INHIBITS CELL-CYCLE PROGRESSION IN NORMAL MYOBLASTSAND FIBROBLASTS

Integrins are alpha beta heterodimeric transmembrane receptors involve d in the regulation of cell growth and differentiation. The beta(1) in tegrin subunit is widely expressed in vivo and is represented by four alternatively spliced cytoplasmic domain isoforms, beta(1)D is a muscl e-specific variant of beta(1) integrin and a predominant beta(1) isofo rm in striated muscles. In the present study we showed that expression of the exogenous beta(1)D integrin in C2C12 myoblasts and NIH 3T3 or REF 52 fibroblasts inhibited cell proliferation. Unlike the case of th e common beta(1)A isoform, adhesion of beta(1)D-transfected C2C12 myob lasts specifically via the expressed integrin did not activate mitogen -activated protein kinases, The beta(1)D-induced growth inhibitory sig nal was shown to occur late in the G(1) phase of the cell cycle, befor e the G(1)-S transition. Ha-(12R)Ras, but not (Delta 22W)Raf-1 oncogen e, was able to overcome completely the beta(1)D-triggered cell growth arrest in NIH 3T3 fibroblasts, Since perturbation of the beta(1)D amin o acid sequence in beta(1)A/beta(1)D chimeric integrins decreased the growth inhibitory signal, the entire cytoplasmic domain of beta(1)D ap peared to be important for this function, However, an interleukin-2 re ceptor-beta(1)D chimera containing the cytoplasmic domain of beta(1)D still efficiently inhibited cell growth, showing that the ectodomain a nd the ligand-binding site in beta(1)D were not required for the growt h inhibitory signal. Together, our data showed a new specific function for the alternatively spliced beta(1)D integrin isoform, Since the on set of beta(1)D expression during myodifferentiation coincides with th e timing of myoblast withdrawal from the cell cycle, the growth inhibi tory properties of beta(1)D demonstrated in this study might reflect t he major function for this integrin in commitment of differentiating s keletal muscle cells in vivo.