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

PloS one

PubMedID: 24759943

Choudhary A, Hu He K, Mertins P, Udeshi ND, Dancík V, Fomina-Yadlin D, Kubicek S, Clemons PA, Schreiber SL, Carr SA, Wagner BK. Quantitative-proteomic comparison of alpha and Beta cells to uncover novel targets for lineage reprogramming. PLoS ONE. 2014;9(4):e95194.
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.