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（由申请方提供）：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性失调的RTK的共同特征，并且是细胞转化的重要贡献者。虽然在某些情况下，结合Cbls的RTK区域的改变是这种逃避的基础，但没有细胞内改变的突变体RTK，如胶质瘤中的EGFR和PDGFR，可能通过其他方式逃避Cbls，并且其致癌潜力的这一方面是本提案的重点。在这种情况下？EGFR、其信号的低强度和主要的单体形式是潜在的近端原因。最近我们已经证明了这一点。EGFR与CbI-SETA/CIN 85复合物不相关，CbI-SETA/CIN 85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/CIN 85复合物之间的相互作用和内化依赖于超过一定阈值的激活，这是什么？EGFR不交叉。因此，我们打算测试的假设，致癌潜力？EGFR主要来源于其持续低水平的单体活性，并探索恢复这种强效胶质瘤癌基因下调的方法。我们打算探索可检验的预测，增加？EGFR活性和/或二聚化将恢复Cbl-SETA/ClN 85复合物的调节，导致泛素化、内化、信号衰减和致癌潜力降低。虽然这样的策略将导致增加通过EGFR的人口信号，这将是短暂的，并可能是不太重要的背景下，高水平的野生型EGFR伴随？大多数胶质母细胞瘤中的EGFR。更重要的是改变和持续的衰减？EGFR信号，其已被证明对胶质瘤的形成有显著贡献。其他RTKs突变体与胶质瘤相关，包括额外的EGFR突变体和最近描述的？我们还将检测这些癌基因与Cbl-SETA/CIN 85复合物的相互作用、泛素化下调率和信号强度。