Aspects of Cadherin/Catenin Complexes

描述(由申请人提供)：这是一个竞争性更新的项目，重点是了解钙粘附素/连环蛋白复合体在调节与肿瘤发生相关的细胞行为中的作用。在这一资助期间，我们将通过探索细胞-细胞和细胞-基质相互作用之间的串扰，扩大我们对钙粘附素复合体影响细胞行为的机制的研究，因为这两种类型的黏附对细胞迁移和侵袭等细胞过程至关重要。特别是，我们的研究将集中在钙粘蛋白/连环蛋白复合体的一个成员，α-连环蛋白，如何协调细胞与细胞之间的黏附与不动蛋白的活性，不动蛋白是一种细胞底物黏附结构，介导肿瘤细胞的侵袭。我们的总体假设是，α-连环蛋白通过与肌动蛋白、细胞骨架成分和信号通路的相互作用，在协调调节细胞-细胞和细胞-基质黏附的细胞信号中发挥核心作用。这一假说源于强大的初步证据，该证据使用了一种α-连环蛋白缺失的人类乳腺癌细胞系，该细胞系在α-连环蛋白重新表达后经历了内陷足部的重塑。我们的具体目标是：1)确定α-连环蛋白是否与不定足的成分直接相互作用；2)检验VASP功能对不定足的维持很重要以及β-连环蛋白的表达调节VASP功能的假说；3)确定α-连环蛋白在调节ERK信号转导中的作用。肿瘤的形成和侵袭是严重的人类健康问题。这项拟议的研究侧重于了解细胞如何协调细胞-细胞和细胞-基质相互作用的变化，当它变得恶性时。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。这里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中一个研究较少的成分。

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.