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 SCFβTrCPmediated ubiquitination and promoted degradation of DYRK1A through an unconserved binding motif (49SDQQVSALS57) lying in the N terminus. Any Ser-Ala substitution in this motif could decrease the binding between DYRK1A and β-transducin repeat containing protein (βTrCP), resulting in stabilization of DYRK1A. We also found DYRK1A protein was elevated in the G0/G1phase and decreased in the S and G2/M phase, which was negatively correlated to βTrCP levels in the HEK293 cell cycle. Knockdown of βTrCP caused arrest of the G0/G1phase, which could be partly rescued by down-regulation of DYRK1A. Our study uncovered a new regulatory mechanism of DYRK1A degradation by SCFβTrCPin HEK293 cell cycle progression.
From the Brain Research Institute.|the Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 10766 Jingshi Road, Jinan 250014, and.
Qiang
Q
Liu
Department of Neurology.
Yu
Y
Tang
National Key Lab of Otolaryngology, and.
Long
L
Chen
Department of Hematology, Qilu Hospital of Shandong University, Jinan 250012.
Na
N
Liu
the Department of Gynecology and Obstetrics, Jinan Central Hospital Affiliated with Shandong University, 105 Jiefang Road, Jinan 250013, China.
Fangfang
F
Lang
National Key Lab of Otolaryngology, and.
Heng
H
Liu
National Key Lab of Otolaryngology, and.
Pin
P
Wang
From the Brain Research Institute, xiulians@gmail.com.|National Key Lab of Otolaryngology, and.
Xiulian
X
Sun
D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D002453:Cell Cycle / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D044843:SKP Cullin F-Box Protein Ligases; D000097603:Dyrk Kinases
Alzheimer's disease; DYRK1A; E3 ubiquitin ligase; SCFβTrCP; cell cycle; protein degradation