ALPHA 6 BETA 4 INTEGRIN & LAMININ 5 IN CELL MIGRATION

描述：上皮细胞迁移对于许多重要的生物学过程至关重要。 这些过程包括伤口愈合、胚胎发生和肿瘤侵袭。上皮 细胞迁移是一个复杂的和协调的过程，涉及细胞外 基质，细胞表面受体，细胞内信号传导途径和 细胞骨架重排这个应用程序的目标是开发一个 包括细胞外环境的细胞迁移的综合模型， 跨膜信号传导和细胞内事件。最近的研究 涉及α-6，β-4整联蛋白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。 这项应用的初步研究表明，β-4上的两个位点 整合素亚基，配体结合位点和TAM信号传导基序，执行 在细胞迁移中起关键作用，影响细胞膜定位， 磷酸化的信号分子，包括FAK和p80。进一步我们表明， 层粘连蛋白5的γ-2和α-3链都被BMP-1/mTld加工，和 这种处理在细胞迁移中也起着关键作用。的 这个应用程序的工作假设是，处理改变的能力， 层粘连蛋白5与整合素受体相互作用，包括α-6，β-4， 进而影响细胞迁移。一个具体的目标将阐明 参与信号通路的分子，α-6，β-4整联蛋白， 通过其β-4配体结合和TAM序列， 迁移另一个具体目标将集中在层粘连蛋白5的加工， 对细胞迁移的影响这个具体目标将研究结构变化， 整合素结合位点的改变和信号通路的改变 这是层粘连蛋白5加工的结果。本申请还介绍了 两种基于无毒肽的抑制剂，其对以下显示出高特异性： BMP-1/mTld.每种抑制剂都显示出阻止层粘连蛋白5加工， 显著抑制体外角质形成细胞和鳞状细胞癌细胞迁移。 因此，这些抑制剂有望成为无毒和特异性抗癌剂 并且，作为额外的具体目标，本申请将利用 抑制剂，以研究层粘连蛋白5加工对细胞迁移的影响， 创伤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.