Regulation of Hippo Signaling by Src-Family Kinases

描述（由申请人提供）：细胞粘附受体在肿瘤进展和转移中起关键作用。虽然在正常上皮组织中细胞紧密粘附，但高级别肿瘤中的细胞仅松散地彼此粘附，肿瘤周边的细胞显示出细胞-细胞粘附和局部组织侵袭的显著丧失。高级别肿瘤中细胞间粘附的减少通常是由重要的细胞-细胞粘附蛋白的表达减少或完全丧失引起的。E-cadherin显然是这种蛋白质的最佳研究实例，并且我们对E-cadherin在肿瘤进展和转移中的机制和作用有广泛的了解。我们的实验室一直致力于了解α-连环蛋白的作用和意义，α-连环蛋白是一种细胞间粘附蛋白，它将细胞膜上的钙粘蛋白和连环蛋白与肌动蛋白细胞骨架连接起来。α-连环蛋白通常在高级别上皮肿瘤中丢失或下调，并且α-连环蛋白的丢失与转移性进展和不良患者预后相关。我们最近证实α-连环蛋白在鳞状细胞癌中具有重要的肿瘤抑制功能。对潜在分子机制的分析揭示了α-连环蛋白和Hippo信号转导通路之间的显著联系。我们目前的初步证据表明，α-连环蛋白在调节表皮干细胞的正常稳态的重要作用。我们还表明，α-连环蛋白的主要信号功能涉及Src家族酪氨酸激酶的活性调节。本研究拟探讨α-catenin在鳞状细胞癌中癌起始细胞形成中的作用，并分析Src家族激酶在Hippo信号转导通路、肿瘤发生和发展中的调控机制和意义。

DESCRIPTION (provided by applicant): Cell adhesion receptors play a critical role in tumor progression and metastasis. While in normal epithelial tissues cells are tightly adhere, cells in high-grade tumors are only loosely attached to each other, with cells at the tumor periphery displaying prominent loss of cell-cell adhesion and local tissue invasion. Decreased intercellular adhesion in high-grade tumors is often caused by a decreased expression or a complete loss of important cell-cell adhesion proteins. E-cadherin is clearly the best-studied example of such a protein and we have extensive knowledge concerning the mechanisms and the role of E-cadherin in tumor progression and metastasis. Our laboratory has being focused on understanding the role and significance of alpha-catenin, a cell-cell adhesion protein that links cadherin and catenins at the cell membrane with the actin cytoskeleton. Alpha-catenin is often lost or down regulated in high-grade epithelial tumors and loss of alpha-catenin correlates with metastatic progression and poor patient prognosis. We have recently demonstrated that alpha-catenin has an important tumor-suppressor function in Squamous Cell Carcinoma. The analysis of potential molecular mechanisms revealed a prominent connection between alpha-catenin and the Hippo signal transduction pathway. We present preliminary evidence demonstrating an important role of alpha-catenin in regulation of normal homeostasis of epidermal stem cells. We also show that the principal signaling function of alpha-catenin involves regulation of the activit of Src-family tyrosine kinases. In this grant application we propose to investigate the role of alpha-catenin in formation of cancer initiating cells in Squamous Cell Carcinoma and analyze the mechanisms and significance of Src-family kinases in regulation of Hippo signal transduction pathway, tumor initiation and progression.