E3 Ligase SCFβTrCP-induced DYRK1A Protein Degradation Is Essential for Cell Cycle Progression in HEK293 Cells

DYRK1A, located on the Down syndrome (DS) critical region of chromosome 21, was found to be overexpressed in brains of DS and Alzheimer's disease individuals. DYRK1A was considered to play important roles in the pathogenesis of DS and Alzheimer's disease; however, the degradation mechanism of DYRK1A was still unclear. In this study, we found that DYRK1A was degraded through the ubiquitin-proteasome pathway in HEK293 cells. The N terminus of DYRK1A that was highly unstable in HEK293 cells contributed to proteolysis of DYRK1A. E3 ligase SCF beta TrCP mediated ubiquitination and promoted degradation of DYRK1A through an unconserved binding motif ((49)SDQQVSALS(57)) lying in the N terminus. Any Ser-Ala substitution in this motif could decrease the binding between DYRK1A and beta-transducin repeat containing protein (beta TrCP), resulting in stabilization of DYRK1A. We also found DYRK1Aprotein was elevated in theG0/G1 phase and decreased in the S and G(2)/M phase, which was negatively correlated to beta TrCP levels in the HEK293 cell cycle. Knockdown of beta TrCP caused arrest of the G(0)/G(1) phase, which could be partly rescued by down-regulation of DYRK1A. Our study uncovered a new regulatory mechanism of DYRK1A degradation by SCF beta TrCP in HEK293 cell cycle progression.