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Quantitative-proteomic comparison of alpha and beta cells to uncover novel targets for lineage reprogramming

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Item Type:Article
Title:Quantitative-proteomic comparison of alpha and beta cells to uncover novel targets for lineage reprogramming
Creators Name:Choudhary, A. and He, K.H. and Mertins, P. and Udeshi, N.D. and Dančík, V. and Fomina-Yadlin, D. and Kubicek, S. and Clemons, P.A. and Schreiber, S.L. and Carr, S.A. and Wagner, B.K.
Abstract: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.
Keywords:Calcium-Calmodulin-Dependent Protein Kinase Kinase, Cell Line, Glucagon-Secreting Cells, Insulin-Secreting Cells, Intracellular Signaling Peptides and Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Proteomics, Animals, Mice
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e95194
Date:23 April 2014
Official Publication:https://doi.org/10.1371/journal.pone.0095194
PubMed:View item in PubMed

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