Role of p120-catenin in cell transformation

p120-连环蛋白在细胞转化中的作用

• 批准号: 8579736
• 负责人: ALBERT B REYNOLDS
• 金额: $ 29.61万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579736
• 关键词: Anchorage-Independent Growth; Binding; Brain Diseases; Cadherins; Cell-Cell Adhesion; Centrosome; Cilia; Colon Carcinoma; Complex; Contact Inhibition; Cytoplasmic Tail; Dependence; Development; E-Cadherin; Elements; Epidermal Growth Factor Receptor; Event; Family; Family member; Growth; Growth Factor; Head; Hereditary Disease; Integrins; Link; Literature; MDCK cell; Malignant Neoplasms; Mediating; Modeling; Molecular; Morphogenesis; Mutation; N-Cadherin; N-terminal; Oncogenes; Oncogenic; PDGFRB gene; Pathogenesis; Pathology; Pathway interactions; Phenotype; Process; Protein Isoforms; Proteins; Receptor Protein-Tyrosine Kinases; Role; Signal Pathway; Signal Transduction; Stress; Structure; Tissues; Tumor Suppressor Proteins; Tyrosine; Vertebrates; base; cell growth; cell transformation; in vivo; inhibitor/antagonist; interest; mouse model; novel; public health relevance; research study; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): p120-catenin (p120) was originally identified as a tyrosine phosphorylated substrate of oncogenic Src and of several prominent Growth Factor (GF)-activated Receptor Tyrosine Kinases (RTKs)(e.g., PDGFR, EGFR, CSF-1R). Over the past decade, p120 has emerged as a master regulator of classical cadherin stability and thus a critical determinant of cell-cell adhesion in most tissues. We have used oncogenic drivers of several downstream RTK signaling pathways to examine the role of p120 in AIG, a phenomenon typically associated with corruption of integrin signaling. Surprisingly, p120 knockdown completely blocks Src- and Rac1- (but not Ras) mediated AIG. The effect is reversed by ROCK inhibitors, consistent with our previous model, and rescuable by p120 isoform-1, but not isoform-3. Thus, we add AIG to the rapidly expanding list of cancer relevant phenotypes that are selectively dependent on isoform-1. However, the mechanism also requires E-cadherin and/or N- cadherin, depending on the oncogenic driver, a result that does not conform to prevailing notions of how AIG occurs. Similar results with respect to tumorigenesis in our APCmin:p120fl/fl mouse model of colon cancer and other observations (see background/significance) demonstrate in vivo relevance, an unappreciated bottleneck in tumor progression, and an alternative interpretation of an extensive pathology literature on p120 expression in cancer. To better appreciate the underlying mechanisms, aims 1 and 2 examine poorly understood relationships between RTK-cadherin and oncogene signaling, and the selective role of p120 isoform-1 in this process. Aim 3 focuses on our discovery of a novel isoform-1 specific p120 binding partner linked to a spectrum of developmental brain disorders. As a potentially unifying hypothesis, we suggest that the interaction connects diverse elements of the p120 literature with emerging roles of the centrosome and cilia in multiple genetic disorders and cancer.

描述（由申请人提供）：p120-连环蛋白（p120）最初被鉴定为致癌Src和几种主要生长因子（GF）激活的受体酪氨酸激酶（RTK）（例如，PDGFR、EGFR、CSF-1R）。在过去的十年中，p120已经成为经典钙粘蛋白稳定性的主要调节因子，因此在大多数组织中是细胞-细胞粘附的关键决定因素。我们已经使用了几个下游RTK信号通路的致癌驱动程序来研究p120在AIG中的作用，这是一种典型的与整合素信号转导受损相关的现象。令人惊讶的是，p120敲低完全阻断Src和Rac 1（但不是Ras）介导的AIG。ROCK抑制剂可逆转该效应，这与我们先前的模型一致，并且可通过p120亚型-1而不是亚型-3进行挽救。因此，我们将AIG添加到选择性依赖于同种型-1的快速扩展的癌症相关表型列表中。然而，该机制还需要E-钙粘蛋白和/或N-钙粘蛋白，这取决于致癌驱动因素，这一结果不符合AIG如何发生的流行观念。在我们的APC min：p120 fl/fl结肠癌小鼠模型中关于肿瘤发生的类似结果和其他观察结果（参见背景/显著性）证明了体内相关性、肿瘤进展中未被认识到的瓶颈以及关于癌症中p120表达的广泛病理学文献的替代解释。为了更好地了解潜在的机制，目的1和2检查RTK-钙粘蛋白和癌基因信号传导之间的关系知之甚少，以及p120亚型-1在这一过程中的选择性作用。目的3集中在我们发现的一种新的异构体-1特异性p120结合伴侣与一系列发育性脑疾病。作为一个潜在的统一的假设，我们认为，相互作用连接的p120文献的不同元素与新兴的中心体和纤毛在多种遗传疾病和癌症的作用。