INTEGRIN ALPHA-1-BETA-1 MEDIATES A UNIQUE COLLAGEN-DEPENDENT PROLIFERATION PATHWAY IN-VIVO

Activation of integrins upon binding to extracellular matrix proteins is believed to be a crucial step for the regulation of cell survival a nd proliferation. We have used integrin alpha 1-null mice to investiga te the role of this collagen receptor in the regulation of cell growth and survival in vivo. alpha 1-deficient animals, which are viable and fertile, have a hypocellular dermis and a deficiency in dermal fibrob last proliferation as embryos. In vitro analysis of alpha 1-null embry onic fibroblasts has revealed that their proliferation rate is markedl y reduced when plated on collagenous substrata, despite normal attachm ent and spreading. Moreover, on the same collagenous matrices, alpha 1 -null fibroblasts fail to recruit and activate the adaptor protein Shc . The failure to activate Shc is accompanied by a downstream deficienc y in recruitment of Grb2 and subsequent mitogen-activated protein kina se activation. Taken together with the growth deficiency observed on c ollagens, this finding indicates that the alpha 1 beta 1 is the sole c ollagen receptor which can activate the Shc mediated growth pathway. T hus, integrin alpha 1 has a unique role among the collagen receptors i n regulating both in vivo and in vitro cell proliferation in collageno us matrices.