SRC AS AN E6AP SUBSTRATE

描述 泛素介导的蛋白质降解是 细胞调节信号网络中的蛋白质组成。 E6AP，最初在豪利实验室被鉴定为人类 人乳头瘤病毒(HPV)16型E6结合蛋白是一种泛素- 蛋白连接酶(E3)在P53降解中的作用在没有HPV16 E6、E6AP的情况下 是一种已知的E3酶，然而，其底物仍然 不清楚。豪利实验室最近的研究发现了几个 E6AP的潜在底物，包括Src家族成员Blk 非受体酪氨酸激酶。E6AP对BLK影响的研究 已经证明E6AP选择性地针对激酶活性形式 用于降解的Blk。这项提案的目标是确定是否 E6AP影响c-Src和V-Src的稳定性。初步数据 表明E6AP与c-Src相互作用实际上是E6AP的底物 如果这种激酶的激活形式被选择性地降解。在……里面 此外，将研究E6AP对v-Src的影响，以确定是否 V-被选择性地降解。此外，E6AP对v-SRC的影响 将被研究以确定v-SRC是否不稳定或能够逃脱 定向降级。人乳头瘤病毒16型E6对E6AP介导的作用 C-Src的降解也将被分析，因为HPV16 E6可能会改变他 E6AP的底物特异性，c-Src的降解也将 分析认为，HPV16E6可能改变E6AP的底物特异性。 总而言之，这些研究将加深我们对人类癌症的理解 通过提供对非受体的细胞转化的洞察力 酪氨酸激酶和人乳头瘤病毒。

DESCRIPTION Ubiquitin-mediated proteolysis is one of the major mechanisms used by the cell to regulate the protein composition of signaling networks. E6AP, which was originally identified in the Howley lab as a human papillomavirus (HPV) 16 E6 binding protein, functions as a ubiquitin- protein ligase (E3) in p53 degradation. In the absence of HPV16 E6, E6AP is known to function as an E3 enzyme, however, its substrates remain unclear. Recent work from the Howley lab has identified several potential substrates for E6AP, including Blk, a member of the Src family of non-receptor tyrosine kinases. Studies of the effects of E6AP on BLK have demonstrated that E6AP selectively targets the kinase active form of Blk for degradation. The goal of this proposal is to determine if E6AP affects the stability of c-Src and V-Src. Preliminary data indicates that E6AP interacts with c-Src is in fact a substrate for E6AP and if the activated forms of this kinase are selectively degraded. In addition, the effects of E6AP on v-Src will be studied to determine if v- are selectively degraded. In addition, the effects of E6AP on v-SRC will be studied to determine if v-SRC is unstable or is able to escape targeted degradation. The effects of HPV16 E6 on E6AP mediated degradation of c-Src will also be analyzed, as HPV16 E6 may alter he substrate specificity of E6AP, degradation of c-Src will also be analyzed, as HPV16 E6 may alter the substrate specificity of E6AP. Together, these studies will further our understanding of human cancer by providing insight into cellular transformation both by non-receptor tyrosine kinases and by human papillomaviruses.