LIGAND INDEPENDENT ONCOGENIC SIGNALING BY ERBB1

ERBB1 的配体独立致癌信号传导

• 批准号: 2906984
• 负责人: NITA J MAIHLE
• 金额: $ 20.39万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-05 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2906984
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; caldesmon; cell transformation; chick embryo; epidermal growth factor; fibroblasts; gene expression; growth factor receptors; guanine nucleotide binding protein; immunoprecipitation; laboratory mouse; laboratory rabbit; ligands; mitogens; oncogenes; oncoproteins; phosphoproteins; phosphorylation; protein binding; protein structure function; protein tyrosine kinase; site directed mutagenesis; thin layer chromatography; tissue /cell culture; western blottings

Transformation by v-ErbB is correlated with the expression of both tissue-specific and transformation-specific phosphorylation events. Moreover, recent evidence suggests that there are qualitative differences between ligand-dependent vs. ligand-independent ErbB signalling pathways. On the basis of these studies, we propose that v-ErbB oncoproteins are not simply constitutively activated EGF-receptors, but rather that these mutant receptors are capable of sending unique and specifically oncogenic signals. In this regard, we have identified a novel, transformation-associated complex of tyrosine phosphoproteins in v-ErbB transformed fibroblasts. This complex is composed of the signal adapter proteins Shc and Grb2, the guanine nucleotide exchange factor Sos, a novel tyrosine phosphorylated form of the cytoskeletal regulatory protein caldesmon, as well as two novel tyrosine phosphorylated proteins (i.e., pp75 and pp72) with no known homologues based on primary sequence information. In this application we propose to focus much of our effort on a careful dissection of the functional role of this complex in v-ErbB-mediated fibroblast transformation. These studies will allow us to determine if components of this novel transformation-associated complex are required for v-ErbB mediated stress fiber disassembly and/or transformation. We believe this intensive analysis of v-ErbB-mediated oncogenic signalling is warranted, based on the extensive body of information available regarding the molecular basis of oncogenic activation of the avian receptor, the stringency of the biological tests to be used in these analyses (transformation of primary cells in culture, and tumorigenicity assays using an avian gene in avian tissues), and based on the premise that oncogenic (i.e., ligand-independent) ErbB1 signalling pathways may be qualitatively distinct from mitogenic (i.e., ligand-dependent) ErbB1 signalling pathways. The ErbB family of proto-oncogenes has been implicated in the etiology and progression of a variety of human malignancies, and the results of these studies may, therefore, have important implications for the diagnosis and treatment of certain human cancers.

V-ErbB的转化与组织特异性和转化特异性磷酸化事件的表达有关。此外，最近的证据表明，配体依赖和配体非依赖的ErbB信号通路之间存在质的差异。在这些研究的基础上，我们认为v-ErbB癌蛋白不是简单的结构性激活的EGF受体，而是这些突变的受体能够发出独特的和特异的致癌信号。在这方面，我们已经在v-ErbB转化的成纤维细胞中发现了一种新的转化相关的酪氨酸磷酸蛋白复合体。该复合体由信号适配蛋白Shc和Grb2、鸟嘌呤核苷酸交换因子SOS、细胞骨架调节蛋白caldesmon的一种新的酪氨酸磷酸化形式以及两种新的酪氨酸磷酸化蛋白(即pp75和pp72)组成，根据一级序列信息，这些蛋白没有已知的同源物。在本申请中，我们建议将主要精力放在仔细剖析该复合体在v-ErbB介导的成纤维细胞转化中的功能作用上。这些研究将使我们能够确定v-ErbB介导的应力纤维分解和/或转化是否需要这种新的转化相关复合体的成分。我们认为，对v-ErbB介导的致癌信号的深入分析是有必要的，基于大量可用信息，这些信息涉及禽类受体致癌激活的分子基础，这些分析中使用的生物学测试的严格性(培养中原代细胞的转化，以及使用禽类组织中的禽类基因进行致瘤性分析)，以及致癌(即配体无关)ErbB1信号通路可能与有丝分裂(即配体依赖)ErbB1信号通路定性不同的前提。原癌基因ErbB家族与多种人类恶性肿瘤的病因和进展有关，因此，这些研究结果可能对某些人类癌症的诊断和治疗具有重要意义。