Abstract
Integrins are alphabeta heterodimeric transmembrane receptors involved in the regulation of cell growth and differentiation. The beta1 integrin subunit is widely expressed in vivo and is represented by four alternatively spliced cytoplasmic domain isoforms. beta1D is a muscle-specific variant of beta1 integrin and a predominant beta1 isoform in striated muscles. In the present study we showed that expression of the exogenous beta1D integrin in C2C12 myoblasts and NIH 3T3 or REF 52 fibroblasts inhibited cell proliferation. Unlike the case of the common beta1A isoform, adhesion of beta1D-transfected C2C12 myoblasts specifically via the expressed integrin did not activate mitogen-activated protein kinases. The beta1D-induced growth inhibitory signal was shown to occur late in the G1 phase of the cell cycle, before the G1-S transition. Ha-(12R)Ras, but not (Delta22W)Raf-1 oncogene, was able to overcome completely the beta1D-triggered cell growth arrest in NIH 3T3 fibroblasts. Since perturbation of the beta1D amino acid sequence in beta1A/beta1D chimeric integrins decreased the growth inhibitory signal, the entire cytoplasmic domain of beta1D appeared to be important for this function. However, an interleukin-2 receptor-beta1D chimera containing the cytoplasmic domain of beta1D still efficiently inhibited cell growth, showing that the ectodomain and the ligand-binding site in beta1D were not required for the growth inhibitory signal. Together, our data showed a new specific function for the alternatively spliced beta1D integrin isoform. Since the onset of beta1D expression during myodifferentiation coincides with the timing of myoblast withdrawal from the cell cycle, the growth inhibitory properties of beta1D demonstrated in this study might reflect the major function for this integrin in commitment of differentiating skeletal muscle cells in vivo.
Highlights
Integrins are a large family of heterodimeric transmembrane cell adhesion receptors [1]
In the present study we showed that expression of the exogenous 1D integrin in C2C12 myoblasts and NIH 3T3 or REF 52 fibroblasts inhibited cell proliferation
Because the efficiency of cell growth arrest depends on the level of the exogenous 1D, the few proliferating 1D-transfected cells might represent a subpopulation of the transfectants with the lower level of 1D expression. These results show that proliferation of normal myoblasts and fibroblasts is drastically inhibited by 1D integrin
Summary
Integrins are a large family of heterodimeric transmembrane cell adhesion receptors [1]. They are involved in many aspects of cell behavior and are known to regulate a number of intracellular signaling pathways [2,3,4]. 1 integrin, the most ubiquitous  subunit, pairs with at least 10 different ␣ subunits to comprise receptors for a wide variety of ECM proteins. It is abundantly expressed in vivo on all proliferating as well as differentiated growth-arrested cell types, excluding red blood cells [1]. Extracellular matrix; BrdUrd, bromodeoxyuridine; MBP, myelin basic protein; mAb, monoclonal antibody; IL2R, interleukin-2 receptor; DMEM, Dulbecco’s modified Eagle’s medium; CHO, Chinese hamster ovary; FBS, fetal bovine serum
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