A role for the integrin alpha v beta 8 in the negative regulation of epithelial cell growth

The control of cell growth is regulated through coordinated responses to gr owth factors and cell-extracellular matrix (ECM) interactions. Integrins, t he major family of cell-ECM receptors, are vital to these coordinated respo nses. Although much is known of the role of integrins in growth: promotion, specific examples of integrin-mediated cell growth inhibition are few. On the basis of our findings that the integrin beta8 subunit is expressed in a irway epithelial cells and is absent in lung cancers, we investigated the r ole and mechanism of the integrin alphav beta8 in mediating growth inhibiti on. When introduced into either a lung or colon carcinoma Cell line, ps inh ibited cell growth without inducing apoptosis. Ligation of alphav beta8 als o induced cell rounding, inhibited focal contact formation, and initiated a n inhibitory signaling pathway as demonstrated by increased expression of t he cyclin-dependent kinase inhibitor p21(Cip1). The cytoplasmic domain of b eta8 was capable of both growth inhibition and causing cell shape changes a s shown by the use of a chimeric integrin construct consisting of the beta8 -cytoplasmic domain coupled to the beta6-extracellular domain. Finally, whe n tested in vivo, beta8 potently inhibited tumor growth in nude mice. Toget her, these results implicate alphav beta8 as a novel growth-regulatory mole cule of epithelial cells.