Regulation of RTKs by the SETA/CIN85 Complex in Glioma

胶质瘤中 SETA/CIN85 复合物对 RTK 的调节

• 批准号: 7104833
• 负责人: OLIVER BOGLER
• 金额: $ 22.02万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104833
• 关键词: CHO cells; astrocytes; athymic mouse; biological signal transduction; chimeric proteins; confocal scanning microscopy; dimer; epidermal growth factor; gene deletion mutation; gene expression; genetic regulation; genetically modified animals; glioma; growth factor receptors; neoplastic transformation; oncogenes; platelet derived growth factor; protein protein interaction; protein structure function; protein tyrosine kinase; receptor binding; transfection; ubiquitin

DESCRIPTION (provided by applicant): Abnormal receptor tyrosine kinase (RTK) activity is an important element in oncogenic transformation. Recently, escape from Cbl-mediated downregulation ubiquitination has been recognized as a common characteristic of RTKs that have undergone oncogenic deregulation, and a significant contributor to cellular transformation. While in some instances alterations in the region of the RTK that binds Cbls underlie this escape, mutant RTKs with no intracellular alterations, such as occur in EGFR and PDGFR in glioma, may evade Cbls by other means, and this aspect of their oncogenic potential is the focus of this proposal. In the case of the ?EGFR, the low intensity of its signal and predominantly monomeric form are potential proximal causes. Recently we have shown that ?EGFR did not associate with the CbI-SETA/CIN85 complex, which is implicated in the internalization of activated RTKs including EGFR. Interaction between wild-type EGFR and the Cbl-SETA/CIN85 complex and internalization were dependent on activation beyond a certain threshold, which ?EGFR did not cross. Therefore we intend to test the hypothesis that the oncogenic potential of ?EGFR derives primarily from its persistent low-level, monomeric activity, and to explore approaches to restoring downregulation of this potent glioma oncogene. We intend to explore the testable prediction that increasing ?EGFR activity and/or dimerization will restore regulation by the Cbl-SETA/ClN85 complex, resulting in ubiquitination, internalization, signal attenuation and reduced oncogenic potential. Although such a strategy would result in increased signaling through the EGFR population, this would be transient, and may be less significant in the context of the high level of wild-type EGFR that accompanies the ?EGFR in most glioblastomas. Much more important is the attenuation of the altered and persistent ?EGFR signal, which has been shown to contribute significantly to the formation of glioma. Other mutants of RTKs are associated with glioma, including additional EGFR mutants and the recently described ?PDGFRa, and we will also examine these oncogenes for their interaction with the Cbl-SETA/CIN85 complex, ubiquitination downregulation rates and signal intensity.

描述（由申请人提供）：受体酪氨酸激酶（RTK）活性异常是致癌转化的重要因素。最近，逃避 Cbl 介导的下调泛素化已被认为是经历致癌失调的 RTK 的一个共同特征，并且是细胞转化的重要贡献者。虽然在某些情况下，结合 Cbl 的 RTK 区域的改变是这种逃逸的基础，但没有细胞内改变的突变 RTK（例如在神经胶质瘤中的 EGFR 和 PDGFR 中发生的情况）可能通过其他方式逃避 Cbl，并且其致癌潜力的这一方面是本提案的重点。就 EGFR 而言，其信号强度低且主要为单体形式是潜在的近端原因。最近我们发现，EGFR 不与 CbI-SETA/CIN85 复合物结合，而 CbI-SETA/CIN85 复合物与包括 EGFR 在内的活化 RTK 的内化有关。野生型 EGFR 和 Cbl-SETA/CIN85 复合物之间的相互作用以及内化依赖于超过某个阈值的激活，而 EGFR 不会跨越该阈值。因此，我们打算测试以下假设：EGFR 的致癌潜力主要源自其持续的低水平单体活性，并探索恢复这种强效神经胶质瘤癌基因下调的方法。我们打算探索可测试的预测，即增加 EGFR 活性和/或二聚化将恢复 Cbl-SETA/ClN85 复合物的调节，从而导致泛素化、内化、信号衰减和降低致癌潜力。尽管这种策略会导致通过 EGFR 群体的信号传导增加，但这将是暂时的，并且在大多数胶质母细胞瘤中伴随 EGFR 的高水平野生型 EGFR 的背景下可能不太显着。更重要的是改变和持续的 EGFR 信号的减弱，该信号已被证明对神经胶质瘤的形成有显着贡献。 RTK 的其他突变体与神经胶质瘤相关，包括其他 EGFR 突变体和最近描述的 ?PDGFRa，我们还将检查这些癌基因与 Cbl-SETA/CIN85 复合物的相互作用、泛素化下调率和信号强度。