Molecular Dissection of Growth Factor Receptor Signaling

描述（由申请人提供）：酪氨酸激酶活性失调与许多人类癌症有关。表皮生长因子受体家族的几个成员在人类肿瘤中被扩增和过度表达，取消它们的活性可以改善预后和生存。虽然受体酪氨酸激酶下游的有丝分裂途径的机制已经被很好地理解，但对于这些增殖信号是如何被关闭的却知之甚少。在蛋白质组学筛选中鉴定EGF受体途径中的分子，我们先前已经鉴定出Odin，这是一种新的酪氨酸磷酸化的适配器蛋白，含有PTB，锚定蛋白和SAM结构域。我们已经证明，过度表达Odin导致抑制生长因子诱导的信号传导和成纤维细胞的增殖。在秀丽隐杆线虫中，基于rnai敲低Odin同源物导致不育，表明这一进化保守分子的重要性。在初步研究中，我们已经确定Grb2是与Odin相互作用的分子。

DESCRIPTION (provided by applicant): Dysregulated tyrosine kinase activity is implicated in a large number of human cancers. Several members of the epidermal growth factor receptor family are amplified and overexpressed in human tumors and abrogation of their activity can lead to improved prognosis and survival. Although the mechanisms underlying the mitogenic pathways downstream of receptor tyrosine kinases are quite well understood, little is known about how these proliferative signals are shut off. In a proteomic screen to identify molecules in the EGF receptor pathway, we have previously identified Odin, a novel tyrosine-phosphorylated adapter protein containing PTB, Ankyrin and SAM domains. We have demonstrated that overexpression of Odin leads to inhibition of growth factor-induced signaling and proliferation in fibroblasts. RNAi-based knockdown of Odin ortholog in C. elegans leads to sterility indicating the importance of this evolutionarily conserved molecule. In preliminary studies, we have identified Grb2 as a molecule that interacts with Odin. We hypothesize that Odin acts as a negative regulator of growth factor receptor signaling by binding to Grb2 and disrupting the Grb2/Sos/Ras complex. Based on our preliminary data demonstrating association of Odin with several proteins in an EGF-inducible fashion, we further hypothesize that different domains of Odin participate in the recruitment of this multiprotein complex, which is crucial for Odin function. Finally, we hypothesize that Odin plays a role in transformation of fibroblasts by activated tyrosine kinases and in mammary gland development and tumor formation. The significance of this proposal is that it will allow us to define the biochemical mechanisms that help downregulate growth factor induced signaling as well as elucidate the in vivo relevance of Odin in mammary tissue. A detailed understanding of such inhibitory mechanisms will be crucial for strategies that target intracellular signaling molecules in the treatment of human cancers.