ALPHA2 BETA1 INTEGRIN: CELL CYCLE PROGRESSION/MIGRATION

α 2 β 1整联蛋白是正常上皮细胞高水平表达的胶原/层粘连蛋白受体。我们已经表明，在上皮恶性肿瘤中，α 2 β 1整合素表达减少或丢失的方式与上皮分化和肿瘤进展的损失。使用一些体外“功能获得”和“功能丧失”模型，我们已经证明了α 2 β 1整合素在正常上皮分化中起着重要作用，并且在某些情况下，可以作为肿瘤抑制因子。我们已经产生了最近的新数据，α 2 β 1整合素刺激细胞增殖和细胞周期进程。此外，α 2整联蛋白亚基胞质结构域独特地响应于表皮生长因子（EGF）以刺激细胞迁移。我们提出，α 2整合素亚基介导的特异性的一个潜在机制是胞质结构域响应激活复杂细胞过程的不同信号通路的能力。我们提出了三个具体的目标，直接确定的机制，α 2 β 1整合素介导的细胞增殖和细胞周期的进展，并确定内的α 2整合素亚基负责细胞周期进程的细胞质尾的元素。我们还将确定α 2整合素响应EGF衍生信号介导细胞迁移的机制。这三个具体目标是：（1）确定α 2 β 1整联蛋白介导的细胞周期进程中涉及的机制，并确定在α 2胞质结构域缺失的情况下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胞质结构域的特定序列元件。(B)确定α 2整联蛋白亚基胞质结构域单独过表达是否能促进或抑制细胞周期进程。(3)确定α 2细胞质尾依赖性EGF刺激的趋化性的结构和机制基础。

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.