Aspects of Cadherin/Catenin Complexes

描述（由申请人提供）：这是一个项目的竞争性更新，重点是了解钙粘蛋白/连环蛋白复合物在调节与肿瘤发生相关的细胞行为中的作用。在此资助期间，我们将扩大我们的调查机制，从而钙粘蛋白复合物影响细胞行为，探索细胞与细胞和细胞与基质之间的相互作用的串扰，因为这两种类型的粘附是至关重要的细胞过程，如迁移和入侵。特别是，我们的研究将集中在钙粘蛋白/连环蛋白复合物的一个成员，α-连环蛋白，如何协调细胞-细胞粘附与侵袭伪足的活性，细胞基质粘附结构，介导肿瘤细胞的侵袭。我们的总体假设是，α-连环蛋白在协调细胞信号中起着核心作用，这些信号通过与肌动蛋白细胞骨架成分和信号通路的相互作用来调节细胞-细胞和细胞-基质粘附。该假设源于使用α-连环蛋白缺失的人乳腺癌细胞系产生的强有力的初步证据，该细胞系响应于α-连环蛋白再表达而经历侵袭伪足的重塑。我们的具体目标是：1）确定α-连环蛋白是否与侵袭性伪足的组分直接相互作用; 2）测试VASP功能对于维持侵袭性伪足是重要的并且β-连环蛋白的表达调节VASP功能的假设;以及3）确定α-连环蛋白在调节ERK信号传导中的作用。肿瘤的形成和侵袭是严重的人类健康问题。拟议的研究重点是了解细胞如何协调细胞与细胞和细胞与基质相互作用的变化，因为它变得恶性。对肿瘤细胞生物学和肿瘤发生机制的基本了解将为开发新的诊断和治疗方法提供基础。本文提出的研究将通过识别参与细胞-细胞和细胞-基质相互作用之间的串扰的途径，以及通过表征β-连环蛋白的信号传导作用来增加我们对癌症生物学的理解，β-连环蛋白是细胞连接的一种未充分研究的组分。

DESCRIPTION (provided by applicant): This is a competing renewal of a project focused on understanding the role of the cadherin/catenin complex in modulating cellular behavior that is relevant to tumorigenesis. In this grant period, we will expand our investigations into the mechanisms whereby cadherin complexes influence cell behavior by exploring crosstalk between cell-cell and cell-matrix interactions, since both types of adhesion are critical to cellular processes like migration and invasion. In particular, our studies will focus on how one member of the cadherin/catenin complex, Alpha-catenin, coordinates cell-cell adhesion with activity of invadopodia, a cell substrate adhesive structure that mediates invasion in tumor cells. Our overall hypothesis is that alpha-catenin plays a central role in coordinating cellular signals that regulate cell-cell and cell-matrix adhesion through its interactions with actin cytoskeletal components and signaling pathways. This hypothesis stems from strong preliminary evidence generated using an alpha-catenin-null human breast cancer cell line that undergoes remodeling of invadopodia in response to alpha-catenin re- expression. Our specific aims are: 1) to determine if alpha-catenin interacts directly with components of invadopodia; 2) to test the hypotheses that VASP function is important for maintenance of invadopodia and that expression of beta-catenin modulates VASP function; and 3) to define the role of alpha-catenin in regulating ERK signaling. Tumor formation and invasion are significant human health problems. The proposed research focuses on understanding how a cell coordinates changes in cell-cell and cell-matrix interactions as it becomes malignant. A basic understanding of tumor cell biology and the mechanisms involved in tumorigenesis will provide a basis for developing new methods for diagnosis and treatment. Studies proposed here will increase our understanding of cancer biology by identifying pathways involved in the cross talk between cell- cell and cell-matrix interactions and by characterizing signaling roles for beta-catenin, which is an understudied component of cellular junctions.