SIGNAL TRANSDUCTION BY EGF RECEPTORS/ERBB FAMILY MEMBERS

表皮生长因子(EGF)受体是 ErbB多肽生长因子受体家族，其成员 包括ErbB1-4(也包括HER1-4)。这个家族中的受体发挥作用 在控制正常细胞生长方面的关键作用，以及 被认为与癌症的异常增殖有关 细胞。例如，ErbB受体家族的成员是 在乳腺癌细胞中经常过表达，而EGF 人脑中的受体(EGFR)常因突变而被激活 癌症。Heregulins构成了一个新发现的EGF家族- 与ErbB家族成员结合并激活的相关多肽。 Hereguline在心脏和神经发育中起着至关重要的作用， 也可能与肿瘤的发生有关。最近，它一直在 确定EGF和Hereguline激活ErbB家族对 作为辅助受体的成员，例如ErbB2/ErbB3 HEREGGIN的合作伙伴。拟议工作的长期目标是 剖析ErbB家族使用的信号转导机制 辅受体，并确定辅受体成分如何在 促进正常和癌细胞的生长。这项建议 重点研究ErbB3蛋白的信号机制，它是 在ErbB家族成员中独一无二的招聘能力 细胞内信号转导蛋白对任一种EGF的响应 或者是HEREGGIN。因为受体磷酸化是一个关键的第一事件 在触发信号募集的受体信号中- 转导系统中酪氨酸残基的磷酸化模式 ErbB3受体将在EGFR/ErbB3的背景下进行检测 ErbB2/ErbB3共受体。其次，通过什么机制 ErbB3独特的结构元素被用于招聘和 磷脂酰肌醇(PI)3-激酶将被激活 调查过了。最后，中美之间的潜在合作 SHC/RAS/丝裂原激活蛋白激酶(MAPK)和PI3-激酶 通路，两个已知被ErbB3激活的关键信号通路， 将通过使用重组ErbB3蛋白进行研究 被设计成选择性地激活这些信号通路中的每一个。 这些通路在DNA刺激中的潜在协作 MAPK的合成、激活和核转位，以及 最近表征的信号转导蛋白的激活 蛋白激酶B(PKB/Akt)，将被检测。通过这些努力，它是 希望对控制两者的因素有更清楚的了解 将实现正常和癌变的细胞生长。

The epidermal growth factor (EGF) receptor is the prototype of the ErbB family of polypeptide growth factor receptors, whose members include ErbB1-4 (also HER1-4). Receptors in this family play critical roles in the control of normal cellular growth, and are believed to be involved in the abnormal proliferation of cancer cells. For example, member so the ErbB receptors family are frequently over expressed in breast cancer cells, and the EGF receptor (EGFR) is often activated by mutation in human brain cancers. The heregulins constitute a newly discovered family of EGF- related polypeptides that bind to and activate ErbB family members. Heregulines play essential roles in cardiac and neural development, and may also be involved in tumorigenesis. Recently it has been determined that EGF and heregulines activate pairs of ErbB family members functioning as coreceptors, for example the ErbB2/ErbB3 heregulin corecptor. The long term goals of the proposed work are to dissect the signal transduction mechanisms used by ErbB family coreceptors, and to determine how corecptor constituents cooperate in the promotion of normal and cancerous cellular growth. This proposal focuses on the signaling mechanisms of the ErbB3 protein, which is unique among ErbB family members in its ability to recruit intracellular signal transducing proteins in response to either EGF or heregulin. Because receptor phosphorylation is a key first event in receptor signaling that triggers the recruitment of signal- transducers, the pattern of tyrosine residue phosphorylation in the ErbB3 receptor will be examined in the contexts of both EGFR/ErbB3 and ErbB2/ErbB3 coreceptors. Secondly, the mechanism by which the unique structural elements of ErbB3 are used in the recruitment and activation of phosphatidylinositiol (PI) 3-kinase will be investigated. Finally, the potential cooperation of the Shc/Ras/mitogen-activate protein kinase (MAPK) and PI 3-kinase pathways, two key signaling pathways know to be activated by ErbB3, will be investigated through the use of recombinant ErbB3 proteins designed to selectively activate each of these signaling pathways. Potential collaboration of these pathways in the stimulation of DNA synthesis, the activation and nuclear translocation of MAPK, and the activation of the recently characterized signal-transducer, protein kinase B (PKB/Akt), will be examined. Through these efforts it is hope that a clearer understanding of the factors that control both normal and cancerous cellular growth will be achieved.