SIGNAL TRANSDUCTION BY EGF RECEPTORS/ERBB FAMILY MEMBERS

表皮生长因子（EGF）受体是表皮生长因子受体的原型。 多肽生长因子受体的ErbB家族，其成员 包括ErbB 1 -4（也是HER 1 -4）。 这个家族的受体 在控制正常细胞生长中起关键作用， 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度表达，EGF 受体（EGFR）通常在人脑中通过突变而激活 癌的 EGF是一种新发现的EGF家族。 结合并激活ErbB家族成员的相关多肽。 调蛋白在心脏和神经发育中起重要作用， 并且还可能参与肿瘤发生。 最近已经 确定EGF和heregulines激活成对的ErbB家族 作为辅助受体的成员，例如ErbB 2/ErbB 3 调蛋白受体 拟议工作的长期目标是 分析ErbB家族的信号转导机制 共同受体，并确定如何共同受体成分合作， 促进正常和癌细胞生长。 这项建议 重点是ErbB 3蛋白的信号传导机制， 在ErbB家族成员中， 细胞内信号转导蛋白对EGF或 或heregulin。 因为受体磷酸化是关键的第一个事件 在受体信号传导中引发了信号的募集- 的酪氨酸残基磷酸化的模式， ErbB 3受体将在EGFR/ErbB 3 和ErbB 2/ErbB 3共受体。 第二， ErbB 3的独特结构元件用于招募， 磷脂酰肌醇（PI）3-激酶的激活将是 研究了 最后，潜在的合作， Shc/Ras/丝裂原活化蛋白激酶（MAPK）和PI 3-激酶 两条关键的信号通路被ErbB 3激活， 将通过使用重组ErbB 3蛋白进行研究 有选择地激活这些信号通路。 这些途径在刺激DNA中的潜在协作 MAPK的合成、活化和核转位，以及 激活最近表征的信号转导蛋白， 激酶B（PKB/Akt）。 通过这些努力， 我希望更清楚地了解控制这两种因素的因素， 将实现正常和癌细胞生长。

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.