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

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

Amit Choudhary, Kaihui Hu He, Philipp Mertins, Namrata D Udeshi, Vlado Dančík, Dina Fomina-Yadlin, Stefan Kubicek, Paul A Clemons, Stuart L Schreiber, Steven A Carr, Bridget K Wagner

PLoS One. 2014 Apr 23;9(4):e95194.

PMID: 24759943

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP376382115	BRD7389		376382-11-5	Price

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