Regulation of RTKs by the SETA/CIN85 Complex in Glioma

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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.