Mammary epithelial cell-cycle progression via the alpha(2)beta(1) integrin- Unique and synergistic roles of the alpha(2) cytoplasmic domain

The alpha (2)beta (1) integrin supports cell-cycle progression of mammary e pithelial cells adherent to type I collagen matrices. Integrin collagen rec eptors containing the alpha (2) cytoplasmic domain stimulated expression of cyclin E and cyclin-dependent kinase (cdk)2, resulting in cyclin E/cdk2 ac tivation in the absence of growth factors other than insulin. Integrin coll agen receptors in which the alpha (2) cytoplasmic domain was replaced by th e alpha (2), cytoplasmic domain or an alpha (2), subunit cytoplasmic domain truncated after the GFFKR sequence failed to stimulate cyclin E/cdk2 activ ation or entry into S phase in the absence of growth factors. Although over expression of cyclins D or E or cdk2 in cells expressing the integrin colla gen receptor with the alpha (1)-integrin cytoplasmic domain did not restore G(1) progression when mammary epithelial cells adhered to type I collagen, co-expression of cyclin E and cdk2 did rescue the ability of the transfect ants to enter S phase. Activation of cyclin E/cdk2 complex by mammary epith elial cells required synergy between adhesion mediated by an integrin colla gen receptor containing the alpha (2)-integrin subunit cytoplasmic domain a nd the insulin receptor.