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

Choudhary, A.; He, K.H.; Mertins, P.; Udeshi, N.D.; Dančík, V.; Fomina-Yadlin, D.; Kubicek, S.; Clemons, P.A.; Schreiber, S.L.; Carr, S.A.; Wagner, B.K.

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., He, K.H., Mertins, P., Udeshi, N.D., Dančík, V., Fomina-Yadlin, D., Kubicek, S., Clemons, P.A., Schreiber, S.L., 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
ISSN:	1932-6203
Publisher:	Public Library of Science
Volume:	9
Number:	4
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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