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相关。 此外，最近的证据表明，配体依赖性与与配体无关ERBB信号通路之间存在质量差异。 在这些研究的基础上，我们建议V-ERBB癌蛋白不仅是组成型激活的EGF受体，而且还可以使这些突变体受体能够发送独特的，特别是致癌信号。 在这方面，我们已经确定了V-ERBB转化的成纤维细胞中酪氨酸磷蛋白的新型，转化相关的复合物。 该复合物由信号衔接蛋白SHC和GRB2，鸟嘌呤核苷酸交换因子SOS组成，SOS是一种新型的酪氨酸磷酸化形式的细胞骨架调节蛋白Caldesmon的磷酸化形式，以及两个新的酪氨酸磷酸化蛋白质（即，基于已知的pp75和PP72），并基于已知的原理。 在此应用中，我们建议将大部分努力集中在仔细解剖该复合物在V-ERBB介导的成纤维细胞转换中的功能作用。 这些研究将使我们能够确定V-ERBB介导的应激纤维拆卸和/或转化是否需要这种新型转化相关的复合物的组成部分。 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 （即，与配体无关的）ERBB1信号通路可能与有丝分裂（即配体依赖性）ERBB1信号通路不同。 ERBB的原始基因家族与各种人类恶性肿瘤的病因和进展有关，因此这些研究的结果可能对某些人类癌症的诊断和治疗具有重要意义。