ALPHA 6 BETA 4 INTEGRIN & LAMININ 5 IN CELL MIGRATION

描述：上皮细胞迁移对许多重要的生物学行为至关重要。 包括伤口愈合、胚胎发育和肿瘤侵袭等过程。上皮性 细胞迁移是一个复杂而协调的过程，涉及细胞外 基质，细胞表面受体，细胞内信号通路和 细胞骨架重排。此应用程序的目标是开发一个 包含细胞外环境的细胞迁移的综合模型， 跨膜信号和细胞内事件。最近的研究表明 涉及α-6，β-4整合素受体及其配体层粘连蛋白5，在 许多肿瘤和特化上皮组织中的细胞迁移/侵袭。 该应用程序的初步研究表明，Beta-4上的两个站点 整合素亚基，配体结合部位和信号基序，执行 在细胞迁移中的关键作用，影响细胞膜的定位 磷酸化的信号分子包括FAK和p80。进一步，我们证明了 层粘连蛋白5的伽马-2和α-3链都被BMP-1/mTLD处理，并且 这一过程在细胞迁移过程中也起着关键作用。这个 这个应用程序的工作假设是，处理改变了 层粘连蛋白5与整合素受体相互作用，包括α-6，β-4，其中 反过来又会影响细胞迁移。一个特定的目标将阐明 α-6，β-4整合素， 通过其β-4配体结合和序列，利用来调节细胞 迁移。另一个具体目标将集中在层粘连蛋白5和 它对细胞迁移的影响。这一具体目标将研究结构性变化， 整合素结合部位的改变和信号通路的改变 这是层粘连蛋白5处理的结果。在此应用程序中还引入了 两种无毒的基于多肽的抑制剂，显示出高度的特异性 BMP-1/mTLD。每种抑制剂都能阻止层粘连蛋白5的加工和 深刻抑制角质形成细胞和鳞癌细胞的体外迁移。 因此，这些抑制剂有望成为无毒和特异的抗癌药物。 并且，作为一个额外的特定目标，此应用程序将利用 研究层粘连蛋白5加工对细胞迁移的影响的抑制剂 伤口愈合和肿瘤侵袭的动物模型系统。

DESCRIPTION: Epithelial cell migration is vital to many important biological processes including wound healing, embryogenesis and tumor invasion. Epithelial cell migration is a complex and coordinated process involving the extracellular matrix, cell surface receptors, intracellular signaling pathways and cytoskeletal rearrangements. The goal of this application is to develop an integrated model of cell migration encompassing the extracellular environment, transmembrane signaling and intracellular events. Recent studies have implicated the alpha-6,beta-4 integrin receptor and its ligand, laminin 5, in cell migration/invasion in many tumors and specialized epithelial tissues. Preliminary studies in this application show that two sites on the beta-4 integrin subunit, the ligand binding site and the TAM signaling motif, perform critical roles in cell migration, affecting the membrane localization of phosphorylated signaling molecules including FAK and p80. Further we show that both gamma-2 and alpha-3 chains of laminin 5 are processed by BMP-1/mTld, and that this processing also performs a critical role in cell migration. The working hypothesis of this application is that processing alters the ability of laminin 5 to interact with integrin receptors, including alpha-6,beta-4, which in turn influences cell migration. One Specific Aim will elucidate the molecules involved in the signaling pathways which alpha-6,beta-4 integrin, through its beta-4 ligand binding and TAM sequences, utilizes to regulate cell migration. The other Specific Aim will focus on the processing of laminin 5 and its effect on cell migration. This Specific Aim will study structural changes, alterations of integrin binding sites, and alterations of signaling pathways that result from laminin 5 processing. Also introduced in this application are two nontoxic peptide based inhibitors, which show a high specificity for BMP-1/mTld. Each inhibitor is shown to prevent laminin 5 processing and profoundly inhibit keratinocyte and squamous carcinoma cell migration in vitro. Thus these inhibitors hold promise as nontoxic and specific anti-cancer agents and, as an additional Specific Aim, this application will utilize the inhibitors to study the effects of laminin 5 processing on cell migration in animal model systems of wound healing and tumor invasion.