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  • The attachment of ubiquitin to RTKs

    2020-09-18

    The attachment of ubiquitin to RTKs, such as EGFR, mediates efficient delivery through the endosome-lysosome system for proteolysis. In this way, RTK degradation enables cessation of signal transduction. A recent siRNA screen identified a number of USPs that can significantly modulate EGFR levels and degradation kinetics [28]. Our data strongly indicate that USP22 plays complex roles in conferring drug resistance in lung ADCs. However, our finding on prevention of endocytosis-mediated EGFR degradation by USP22 reveals one vital aspect of USP22\'s diverse functions. Although more intensive investigation is necessary, our study provides a plausible explanation for how USP22 promotes EGFR-TKIs resistance in EGFR-mutant lung adenocarcinoma. Down-regulation of EGFR-dependent signaling is achieved by internalization of activated EGFR and its degradation in lysosome [29]. Endosomal sorting triggered by ubiquitination of EGFR can also be attenuated by DUBs. There are multiple ubiquitin protein ligases (E3s) and accompanying DUBs that function in the endocytic pathway as regulators of membrane protein trafficking and degradation [30]. Three mammalian DUBs, AMSH, UBPY and USP2a, have been assessed in terms of their effect on EGFR ubiquitination and degradation. While both AMSH [31] and UBPY [32,33] show deubiquitinating activity on Ubn-EGFR, the effects of these DUBs on EGFR down-regulation have been controversial. Some studies showed that AMSH [31] and UBPY [32,33] prevent EGFR down-regulation by deubiquitinating EGFR. USP2a antagonizes endocytosis-mediated EGFR degradation and thus amplifies signaling activity from the receptor [15]. Nevertheless, both AMSH [31,34,35] and UBPY [32,33,[36], [37], [38]] have been reported to increase EGFR down-regulation. In the present study, we showed that USP22 localized to late endosomes, decreased Ubn-EGFR, and promoted degradation of EGFR in a proteasome-dependent pathway, which eventually increased tgf beta membrane-localized EGFR. Taken together, we propose a working model that helps explain the potential roles of USP22 in stabilizing EGFR by reducing endocytosis-mediated degradation (Fig. 9). In this model, late endosome-localized USP22 deubiquitinates EGFR and impedes sorting of EGFR to the lysosome, thus sustaining the trafficking of EGFR to the plasma membrane (Figs. 6 and 9). We demonstrated that the specific role of USP22 in enhancing EGFR recycling back to the plasma membrane. USP22 might interact directly with the components of ESCRTs (endosomal sorting complexes required for transports), such as STAM2 and Eps15, as has been shown for other DUBs [32,[37], [38], [39]]. It remains to be determined if some ESCRT components are substrates of USP22. However, since USP22 was shown to bind to late endosomes, we speculate that USP22 acts in the late steps of docking/assembly (ESCRT-II/III) rather than in the early steps of ESCRTs recruitment/docking (ESCRT-0/I). USP22 shows oncogenic properties and is over-expressed in lung ADCs. We show here that overexpression of USP22 prevents EGFR down-regulation, while shRNA mediated silencing of USP22 enhances EGFR degradation. It is worth noting that an increase in activated EGFR (p-EGFR) and enhanced EGFR downstream signaling were observed in cells with high levels of USP22. Accumulating studies have revealed that STAT3, AKT/mTOR, and MEK/ERK pathways are actively involved in many aspects of tumorigenesis [[40], [41], [42], [43], [44], [45]]. Thus, stabilization and activation of EGFR by USP22 are likely to be important factors in the mechanism underlying the oncogenicity and drug-resistance in EGFR-mutant lung ADCs. In support of this point, a correlation between USP22 and EGFR expression was observed in human EGFR-mutant lung ADC (Fig. 8B).
    Disclosure of conflicts of interest
    Acknowledgements
    Introduction Lung cancer is the leading cause of cancer-related deaths, being responsible for 27% of cancer mortality. Within lung cancer, adenocarcinoma represents the most prevalent histological type. Several driver alterations that are responsible for the initiation and progression of these tumors have been identified. Of these, one of the most relevant at the therapeutic level is mutation in the tyrosine kinase receptor EGFR, which is found in up to 20% of adenocarcinomas in white cohorts and in up to 30% to 50% of patients of Asiatic origin.1, 2 The discovery of these alterations and the development of EGFR inhibitors have significantly improved outcomes for such patients. However, in spite of the benefits achieved by EGFR inhibition, tumor relapse is universal and there are patients whose tumors harbor unknown EGFR mutations or exhibit EGFR activation without mutations, thereby excluding them as candidates for these therapies.4, 5, 6 The identification of predictive biomarkers for EGFR therapy and novel therapeutic approaches with higher efficacy for treatment of these tumors is therefore crucial.