ALPHA2 BETA1 INTEGRIN: CELL CYCLE PROGRESSION/MIGRATION

alpha2beta1整合素是一种在正常上皮细胞中高水平表达的胶原/层粘连蛋白受体。我们已经证明，在上皮性恶性肿瘤中，alpha2beta1整合素表达的减少或缺失与上皮分化和肿瘤进展的丧失有关。通过许多体外“功能获得”和“功能丧失”模型，我们已经证明了alpha2beta1整合素在正常上皮分化中起重要作用，并且在某些情况下可以作为肿瘤抑制因子。我们最近获得的新数据表明，alpha2beta1整合素刺激细胞增殖和细胞周期进展。此外，α 2整合素亚基细胞质结构域对表皮生长因子（EGF）有独特的响应，以刺激细胞迁移。我们提出，由α 2整合素亚基介导的特异性的一个潜在机制是细胞质结构域对激活复杂细胞过程的不同信号通路作出反应的能力。我们提出了三个具体目标，以直接确定α 2 β 1整合素介导细胞增殖和细胞周期进程的机制，并确定α 2整合素亚基细胞质尾部负责细胞周期进程的元件。我们还将确定alpha2整合素响应EGF衍生信号介导细胞迁移的机制。三个具体目标是：(1)确定参与alpha2beta1整合素介导的细胞周期进程的机制，并确定在缺乏alpha2细胞质结构域时导致细胞周期停滞的细胞周期缺陷。(2) (A)通过缺失和突变分析鉴定细胞增殖所需的α 2细胞质结构域的特定序列元件。(B)确定单独过表达α 2整合素亚基细胞质结构域是否能促进或抑制细胞周期进程。(3)明确α 2细胞质尾依赖性egf刺激趋化的结构和机制基础。

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.