ALPHA2 BETA1 INTEGRIN: CELL CYCLE PROGRESSION/MIGRATION

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The alpha2beta1 integrin is a collagen/laminin receptor expressed at high levels by normal epithelial cells. We have shown that in epithelial malignancies, the alpha2beta1 integrin expression is diminished or lost in a manner that correlates with loss of epithelial differentiation and tumor progression. Using a number of in vitro "gain of function" and "loss of function" models, we have demonstrated that the alpha2beta1 integrin plays an important role in normal epithelial differentiation and, under some circumstances, can serve as a tumor suppressor. We have generated recent new data that the alpha2beta1 integrin stimulates cell proliferation and cell cycle progression. In addition, the alpha2 integrin subunit cytoplasmic domain uniquely responds to epidermal growth factor (EGF) for stimulating cell migration. We propose that one potential mechanism for specificity mediated by the alpha2 integrin subunit is the ability of the cytoplasmic domain to respond to distinct signaling pathways that active complex cellular processes. We propose three specific aims to directly determine the mechanisms by which the alpha2beta1 integrin mediates cell proliferation and cell cycle progression and to define the elements within the cytoplasmic tail of the alpha2 integrin subunit responsible for cell cycle progression. We also will determine the mechanism by which the alpha2 integrin responds to EGF derived signals to mediate cell migration. The three specific aims are: (1) To define the mechanisms involved in alpha2beta1 integrin mediated cell cycle progression and to define the cell cycle defect responsible for cell cycle arrest in the absence of the alpha2 cytoplasmic domain. (2) (A) To identify by deletional and mutational analysis of specific sequence elements of the alpha2 cytoplasmic domain required for cell proliferation. (B) To determine if over-expression of the alpha2 integrin subunit cytoplasmic domain alone can promote or inhibit cell cycle progression. (3) To define the structural and mechanistic basis underlying alpha2 cytoplasmic tail-dependent EGF-stimulated chemotaxis.