PDX1型
磷酸蛋白质组学
信号转导
β细胞
细胞生物学
生物
胰岛
内分泌学
内科学
分泌物
胰岛素
磷酸化
蛋白激酶A
小岛
医学
蛋白质磷酸化
作者
Francesca Sacco,Anett Seelig,Sean J. Humphrey,Natalie Krahmer,Francesco Volta,Alessio Reggio,Piero Marchetti,Jantje M. Gerdes,Matthias Mann
出处
期刊:Cell Metabolism
[Elsevier]
日期:2019-06-01
卷期号:29 (6): 1422-1432.e3
被引量:69
标识
DOI:10.1016/j.cmet.2019.02.012
摘要
Progressive decline of pancreatic beta cell function is central to the pathogenesis of type 2 diabetes. Protein phosphorylation regulates glucose-stimulated insulin secretion from beta cells, but how signaling networks are remodeled in diabetic islets in vivo remains unknown. Using high-sensitivity mass spectrometry-based proteomics, we quantified 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls, revealing drastic remodeling of key kinase hubs and signaling pathways. Integration with a literature-derived signaling network implicated GSK3 kinase in the control of the beta cell-specific transcription factor PDX1. Deep phosphoproteomic analysis of human islets chronically treated with high glucose demonstrated a conserved glucotoxicity-dependent role of GSK3 kinase in regulating insulin secretion. Remarkably, the ability of beta cells to secrete insulin in response to glucose was rescued almost completely by pharmacological inhibition of GSK3. Thus, our resource enables investigation of mechanisms and drug targets in type 2 diabetes.
科研通智能强力驱动
Strongly Powered by AbleSci AI