Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming

• Main Authors: Choudhary, Amit (Author), Hu He, Kaihui (Author), Mertins, Philipp (Author), Udeshi, Namrata D. (Author), Dancik, Vlado (Author), Fomina-Yadlin, Dina (Author), Kubicek, Stefan (Author), Clemons, Paul A. (Author), Schreiber, Stuart L. (Author), Wagner, Bridget K. (Author), Carr, Steven A (Author)
• Other Authors: Koch Institute for Integrative Cancer Research at MIT (Contributor), Carr, Steven A. (Contributor)
• Format: Article
• Language: English
• Published: Public Library of Science, 2014-06-20T14:33:14Z.
• Subjects: Article
• Online Access: Get fulltext

Type-1 diabetes (T1D) is an autoimmune disease in which insulin-secreting pancreatic beta cells are destroyed by the immune system. An emerging strategy to regenerate beta-cell mass is through transdifferentiation of pancreatic alpha cells to beta cells. We previously reported two small molecules, BRD7389 and GW8510, that induce insulin expression in a mouse alpha cell line and provide a glimpse into potential intermediate cell states in beta-cell reprogramming from alpha cells. These small-molecule studies suggested that inhibition of kinases in particular may induce the expression of several beta-cell markers in alpha cells. To identify potential lineage reprogramming protein targets, we compared the transcriptome, proteome, and phosphoproteome of alpha cells, beta cells, and compound-treated alpha cells. Our phosphoproteomic analysis indicated that two kinases, BRSK1 and CAMKK2, exhibit decreased phosphorylation in beta cells compared to alpha cells, and in compound-treated alpha cells compared to DMSO-treated alpha cells. Knock-down of these kinases in alpha cells resulted in expression of key beta-cell markers. These results provide evidence that perturbation of the kinome may be important for lineage reprogramming of alpha cells to beta cells.
Juvenile Diabetes Research Foundation International (JDRF 17-2008-1030)
Juvenile Diabetes Research Foundation International (JDRF 17-2011-260)
Harvard University. Society of Fellows