Regulation of RTKs by the SETA/CIN85 Complex in Glioma

描述(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介导的泛素化被认为是经历了癌基因去调控的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CBLs的RTK区域的变化是这种逃逸的基础，但没有细胞内变化的突变RTK，例如在胶质瘤中发生在EGFR和PDGFR中，可能通过其他方式避开CBLs，这方面的致癌潜力是本研究的重点。在？EGFR的情况下，其信号的低强度和主要的单体形式是潜在的近端原因。最近我们发现？EGFR不与CBI-SETA/CIN85复合体结合，而CBI-SETA/CIN85复合体与包括EGFR在内的活化RTK的内化有关。野生型EGFR与Cb1-SETA/CIN85复合体之间的相互作用和内化依赖于超过一定阈值的激活，而EGFR不会超过这个阈值。因此，我们打算验证这一假设，即？EGFR的致癌潜力主要来自其持续的低水平单体活性，并探索恢复这一强大的胶质瘤癌基因下调的方法。我们打算探索可检验的预测，即增加EGFR活性和/或二聚化将恢复Cbl-SETA/ClN85复合体的调节，导致泛素化、内部化、信号衰减和致癌潜力降低。虽然这样的策略将导致通过EGFR群体的信号增加，但这是暂时的，在大多数胶质母细胞瘤中伴随？EGFR的野生型EGFR水平较高的情况下，这可能不那么显著。更重要的是改变的和持续的？EGFR信号的衰减，这已被证明是胶质瘤形成的重要因素。RTK的其他突变与胶质瘤有关，包括其他EGFR突变和最近描述的？PDGFRA，我们还将检测这些癌基因与Cbl-SETA/CIN85复合体的相互作用、泛素化下调速率和信号强度。

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.