Brain-selective kinase 2 (BRSK2) phosphorylation on PCTAIRE1 negatively regulates glucose-stimulated insulin secretion in pancreatic β-cells.
Brain-selective kinase 2 (BRSK2) has been shown to play an essential role in neuronal polarization. In the present study, we show that BRSK2 is also abundantly expressed in pancreatic islets and MIN6 β-cell line. Yeast two-hybrid screening, GST fusion protein pull-down, and co-immunoprecipitation assays reveal that BRSK2 interacts with CDK-related protein kinase PCTAIRE1, a kinase involved in neurite outgrowth and neurotransmitter release. In MIN6 cells, BRSK2 co-localizes with PCTAIRE1 in the cytoplasm and phosphorylates one of its serine residues, Ser-12. Phosphorylation of PCTAIRE1 by BRSK2 reduces glucose-stimulated insulin secretion (GSIS) in MIN6 cells. Conversely, knockdown of BRSK2 by siRNA increases serum insulin levels in mice. Our results reveal a novel function of BRSK2 in the regulation of GSIS in β-cells via a PCTAIRE1-dependent mechanism and suggest that BRSK2 is an attractive target for developing novel diabetic drugs.
State Key Laboratory of Genetic Engineering, School of Life Science, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
Xin-Ya
XY
Chen
Xiu-Ting
XT
Gu
Hexige
H
Saiyin
Bo
B
Wan
Yu-Jing
YJ
Zhang
Jing
J
Li
Ying-Li
YL
Wang
Rui
R
Gao
Yu-Fan
YF
Wang
Wei-Ping
WP
Dong
Sonia M
SM
Najjar
Chen-Yu
CY
Zhang
Han-Fei
HF
Ding
Jun O
JO
Liu
Long
L
Yu
D000818:Animals; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; C507732:Brsk2 protein, human; C496825:Brsk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; C089463:PCTAIRE-1 protein kinase; D005947:Glucose