Role of p120-catenin in cell transformation

描述（由申请人提供）：p120-catenin （p120）最初被确定为致癌Src和几种突出的生长因子（GF）激活的受体酪氨酸激酶（rtk）的酪氨酸磷酸化底物。， pdgfr, egfr, csf-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。我们利用几个下游RTK信号通路的致癌驱动因素来研究p120在AIG中的作用，这一现象通常与整合素信号通路的破坏有关。令人惊讶的是，p120敲低完全阻断Src-和Rac1-介导的AIG（但不包括Ras）。与我们之前的模型一致，ROCK抑制剂可以逆转这种效应，并且p120 -1异构体可以挽救这种效应，而p120 -3异构体则不能。因此，我们将AIG添加到快速扩展的选择性依赖于同型异构体-1的癌症相关表型列表中。然而，这一机制也需要e -钙粘蛋白和/或N-钙粘蛋白，这取决于致癌驱动因素，这一结果不符合关于AIG如何发生的普遍观点。在我们的APCmin:p120fl/fl结肠癌小鼠模型和其他观察（见背景/意义）中，关于肿瘤发生的类似结果证明了体内相关性，肿瘤进展中未被重视的瓶颈，以及对p120在癌症中表达的广泛病理文献的另一种解释。为了更好地了解潜在的机制，目的1和2研究了rtk -钙粘蛋白与癌基因信号传导之间的关系，以及p120亚型-1在这一过程中的选择性作用。Aim 3的重点是我们发现了一种与一系列发育性脑疾病相关的新型异构体-1特异性p120结合伙伴。作为一种潜在的统一假设，我们认为p120文献中的不同元素与中心体和纤毛在多种遗传疾病和癌症中的新角色之间存在相互作用。

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.