Regulation of RTKs by the SETA/CIN85 Complex in Glioma

描述（由申请人提供）：异常受体酪氨酸激酶（RTK）活性是致癌转化的重要因素。最近，从cbl介导的下调泛素化中逃脱已被认为是经历了致癌解除管制的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逸的基础，但没有细胞内改变的突变RTK，如胶质瘤中的EGFR和PDGFR，可能通过其他方式逃避Cbls，而这方面的致癌潜力是本提案的重点。在？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？EGFR不与CbI-SETA/CIN85复合物相关，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与Cbl-SETA/CIN85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。EGFR没有交叉。因此，我们打算测试的假设，致癌潜力？EGFR主要来源于其持续的低水平单体活性，并探索恢复这种强效胶质瘤癌基因下调的方法。我们打算探索可测试的预测，增加？EGFR活性和/或二聚化将恢复Cbl-SETA/ClN85复合体的调控，导致泛素化、内化、信号衰减和致癌潜力降低。尽管这样的策略会导致EGFR群体信号的增加，但这将是短暂的，并且在伴随高水平野生型EGFR的背景下可能不那么重要。大多数胶质母细胞瘤中的EGFR。更重要的是改变和持久的衰减？EGFR信号，已被证明对胶质瘤的形成有重要作用。rtk的其他突变体与胶质瘤有关，包括额外的EGFR突变体和最近描述的？我们还将检查这些致癌基因与ccl - seta /CIN85复合体的相互作用，泛素化下调率和信号强度。

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.