State Key Laboratory of Genetic Engineering, School of Life Science, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
J Biol Chem. 2012 Aug 31;287(36):30368-75. doi: 10.1074/jbc.M112.375618. Epub 2012 Jul 13.
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.
脑选择性激酶 2（BRSK2）已被证明在神经元极化中发挥重要作用。在本研究中，我们表明 BRSK2 也在胰腺胰岛和 MIN6 β细胞系中大量表达。酵母双杂交筛选、GST 融合蛋白下拉和共免疫沉淀实验表明，BRSK2 与 CDK 相关蛋白激酶 PCTAIRE1 相互作用，PCTAIRE1 是一种参与神经突生长和神经递质释放的激酶。在 MIN6 细胞中，BRSK2 与 PCTAIRE1 在细胞质中共定位，并磷酸化其一个丝氨酸残基 Ser-12。BRSK2 对 PCTAIRE1 的磷酸化降低了 MIN6 细胞中葡萄糖刺激的胰岛素分泌（GSIS）。相反，siRNA 敲低 BRSK2 会增加小鼠血清胰岛素水平。我们的结果揭示了 BRSK2 通过 PCTAIRE1 依赖性机制在调节β细胞中的 GSIS 中的新功能，并表明 BRSK2 是开发新型糖尿病药物的有吸引力的靶标。
