LIGAND INDEPENDENT ONCOGENIC SIGNALING BY ERBB1

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，在配体依赖性和不依赖配体的ErbB信号通路之间存在定性差异。在这些研究的基础上，我们提出v-ErbB癌蛋白不仅仅是组成型激活的egf受体，而是这些突变受体能够发送独特的特异性致癌信号。在这方面，我们在v-ErbB转化成纤维细胞中发现了一种新的转化相关的酪氨酸磷酸化蛋白复合物。该复合物由信号转换蛋白Shc和Grb2、鸟嘌呤核苷酸交换因子Sos、一种新的酪氨酸磷酸化形式的细胞骨架调节蛋白caldesmon以及两种新的酪氨酸磷酸化蛋白（即pp75和pp72）组成，基于初级序列信息，它们没有已知的同源物。在这个应用中，我们建议将我们的大部分精力集中在仔细解剖这个复合物在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这种新型转化相关复合物的成分是否需要v-ErbB介导的应力纤维分解和/或转化。我们认为，基于有关禽类受体致癌激活的分子基础的大量现有信息，基于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，以及在禽类组织中使用禽类基因进行致瘤性分析），以及基于致癌(即：ErbB1信号通路可能与有丝分裂（即配体依赖性）ErbB1信号通路在质上不同。ErbB家族的原癌基因与多种人类恶性肿瘤的病因学和进展有关，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。

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.