Dual specificity tyrosine phosphorylation regulated kinase 1A, DYRK1A, functions in multiple cellular pathways, including signaling, endocytosis, synaptic transmission, and transcription. Alterations in dosage of DYRK1A leads to defects in neurogenesis, cell growth, and differentiation, and may increase the risk of certain cancers. DYRK1A localizes to a number of subcellular structures including vesicles where it is known to phosphorylate a number of proteins and regulate vesicle biology. However, the mechanism by which it translocates to vesicles is poorly understood. Here we report the discovery of TRAF2, an E3 ligase, as an interaction partner of DYRK1A. Our data suggest that TRAF2 binds to PVQE motif residing in between the PEST and histidine repeat domain (HRD) of DYRK1A protein, and mediates K63-linked ubiquitination of DYRK1A. This results in translocation of DYRK1A to the vesicle membrane. DYRK1A increases phosphorylation of Sprouty 2 on vesicles, leading to the inhibition of EGFR degradation, and depletion of TRAF2 expression accelerates EGFR degradation. Further, silencing of DYRK1A inhibits the growth of glioma cells mediated by TRAF2. Collectively, these findings suggest that the axis of TRAF2-DYRK1A-Sprouty 2 can be a target for new therapeutic development for EGFR-mediated human pathologies.
基金：
Major Basic Research Project of Science and
Technology of Yunnan (202001BC070001) to LPBR, and in part by National Natural
Science Foundation of China (31471206) to M.M., by Project funded by China
Postdoctoral Science Foundation to P.Z. Y.Z., M.P.W., and L.F. are supported by The
Stowers Institute for Medical Research.
第一作者机构：[1]Shanghai Jiao Tong Univ, Tongren Hosp, Hongqiao Inst Med, Fac Basic Med,Sch Med, Shanghai, Peoples R China[2]Shanghai Jiao Tong Univ, Dept Biochem & Mol Cell Biol, Shanghai Key Lab Tumor Microenvironm & Inflammat, Sch Med, Shanghai, Peoples R China[3]Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Gen Surg, Sch Med, Shanghai, Peoples R China
通讯作者：
通讯机构：[1]Shanghai Jiao Tong Univ, Tongren Hosp, Hongqiao Inst Med, Fac Basic Med,Sch Med, Shanghai, Peoples R China[2]Shanghai Jiao Tong Univ, Dept Biochem & Mol Cell Biol, Shanghai Key Lab Tumor Microenvironm & Inflammat, Sch Med, Shanghai, Peoples R China[4]Kunming Univ Sci & Technol, Inst Primate Translat Med, State Key Lab Primate Biomed Res, Kunming, Yunnan, Peoples R China
推荐引用方式(GB/T 7714)：
Zhang Pengshan,Zhang Zhe,Fu Yinkun,et al.K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR[J].CELL DEATH & DISEASE.2021,12(6):doi:10.1038/s41419-021-03887-2.
APA：
Zhang, Pengshan,Zhang, Zhe,Fu, Yinkun,Zhang, Ying,Washburn, Michael P....&Mohan, Man.(2021).K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR.CELL DEATH & DISEASE,12,(6)
MLA：
Zhang, Pengshan,et al."K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR".CELL DEATH & DISEASE 12..6(2021)
生物学