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-catenin（P120）最初被鉴定为致癌SRC的酪氨酸磷酸化底物和几种突出生长因子（GF）激活受体酪氨酸激酶（RTKS）（例如， 1r）。在过去的十年中，P120已成为经典钙粘蛋白稳定性的主要调节剂，因此是大多数组织中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器来检查p120在AIG中的作用，AIG是一种与整合素信号损坏有关的现象。令人惊讶的是，P120敲低完全阻止了SRC-和Rac1-（而不是RAS）介导的AIG。岩石抑制剂与我们以前的模型一致，并且可以由P120同工型1挽救，而不是同工型3。因此，我们将AIG添加到癌症相关表型的快速扩展列表中，这些表型有选择地依赖于同工型-1。但是，该机制还需要E-钙粘蛋白和/或N-钙粘着蛋白，具体取决于致癌驱动力，这一结果不符合AIG发生的盛行概念。在我们的APCMIN中，关于肿瘤发生的相似结果：结肠癌的P120FL/FL小鼠模型和其他观察结果（请参阅背景/意义）在体内相关性，肿瘤进展中未批准的瓶颈以及对P120扩展病理文献的替代解释癌症的表达。为了更好地理解潜在的机制，目标1和2检查了RTK-钙粘着蛋白和癌基因信号传导之间的关系较少，以及P120同工-1在此过程中的选择性作用。 AIM 3的重点是我们发现与一系列发育脑疾病相关的新型ISOUMOR-1特异性P120结合伴侣。作为一个潜在的统一假设，我们建议这种相互作用将P120文献的各种要素与中心体和纤毛在多种遗传疾病和癌症中的新兴作用联系起来。