TRANSFORMATION SPECIFIC SIGNALING MEDIATED BY VERBS

描述：禽红母细胞增生症病毒的v-erbB癌基因 编码具有酪氨酸激酶活性的截短生长因子受体。 这种病毒癌基因的表达会导致纤维肉瘤、红白血病和 血管肉瘤。对信号转导机制的理解 V-ErbB癌蛋白将提供对酪氨酸激酶信号的洞察 转导途径，形成转化专一性 多蛋白复合体，并有很大的潜力提供对 人类恶性肿瘤的分子生物学。随着这些长期目标的实现， 请记住，本提案中概述的实验将使用具有良好特性的、 V-ErbB的转化特异性结构突变体分解酪氨酸 转化成纤维细胞中的激酶信号通路。这种方法具有 已经揭示了一种转化特异性多蛋白的形成 V-ErbB转化成纤维细胞中的信号复合体。这个建筑群是 由两个信号转接子分子(SHC和Grb2)组成，鸟嘌呤 核苷酸交换因子(SOS)，一种酪氨酸磷酸化形式的 细胞骨架调节蛋白钙调蛋白和一种新的酪氨酸 磷酸化蛋白(Pp75)。需要检验的假设是， V-ErbB启动的致癌信号通过 SHC-Grb2-SOS-caldesmon-pp75复合体，酪氨酸磷酸化 钙调蛋白和pp75参与锚定非依赖性的调节 生长和致瘤性。这项研究的具体目的是：(I) 确定钙调蛋白与多蛋白结合的机制 复合体，(Ii)确定Caldesmon在v-ErbB介导的功能中的作用 转化，以及(Iii)表征了新的75kd酪氨酸 这个信号复合体中的磷酸化蛋白质。

DESCRIPTION: The v-erbB oncogene of the avian erythroblastosis virus encodes a truncated growth factor receptor with tyrosine kinase activity. Expression of this viral oncogene causes fibrosarcomas, erythroleukemias and hemangiosarcomas. Understanding the mechanisms of signal transduction by the v-ErbB oncoprotein will offer insights into tyrosine kinase signal transduction pathways, into the formation of transformation-specific multiprotein complexes, and has great potential to offer insights into the molecular biology of human malignancies. With these long-term goals in mind, the experiments outlined in this proposal will use well-characterized, transformation-specific, structural mutants of v-ErbB to dissect tyrosine kinase signaling pathways in transformed fibroblasts. This approach has already revealed the formation of a transformation-specific multiprotein signaling complex in v-ErbB transformed fibroblasts. This complex is composed of two signal adapter molecules (SHC and GRB2), a guanine nucleotide exchange factor (SOS), a tyrosine phosphorylated form of the cytoskeletal regulatory protein caldesmon, and a novel tyrosine phosphorylated protein (pp75). The hypothesis to be tested is that the oncogenic signals initiated by v-ErbB are transduced through the SHC-GRB2-SOS-caldesmon-pp75 complex, and that tyrosine phosphorylated caldesmon and pp75 participate in the regulation of anchorage-independent growth and tumorigenicity. The specific aims of this study are to (I) determine the mechanism of association of caldesmon with the multiprotein complex, (ii) define the functional role of caldesmon in v-ErbB mediated transformation, and (iii) characterize the novel 75 kd tyrosine phosphorylated protein in this signaling complex.