Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming
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, B...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/88043 https://orcid.org/0000-0002-7203-4299 |
| _version_ | 1826216115368361984 |
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| author | Choudhary, Amit Hu He, Kaihui Mertins, Philipp Udeshi, Namrata D. Dancik, Vlado Fomina-Yadlin, Dina Kubicek, Stefan Clemons, Paul A. Schreiber, Stuart L. Wagner, Bridget K. Carr, Steven A |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Choudhary, Amit Hu He, Kaihui Mertins, Philipp Udeshi, Namrata D. Dancik, Vlado Fomina-Yadlin, Dina Kubicek, Stefan Clemons, Paul A. Schreiber, Stuart L. Wagner, Bridget K. Carr, Steven A |
| author_sort | Choudhary, Amit |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:42:33Z |
| format | Article |
| id | mit-1721.1/88043 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:42:33Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/880432022-09-29T20:54:59Z Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming Choudhary, Amit Hu He, Kaihui Mertins, Philipp Udeshi, Namrata D. Dancik, Vlado Fomina-Yadlin, Dina Kubicek, Stefan Clemons, Paul A. Schreiber, Stuart L. Wagner, Bridget K. Carr, Steven A Koch Institute for Integrative Cancer Research at MIT Carr, Steven A. 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 2014-06-20T14:33:14Z 2014-06-20T14:33:14Z 2014-04 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/88043 Choudhary, Amit, Kaihui Hu He, Philipp Mertins, Namrata D. Udeshi, Vlado Dancik, Dina Fomina-Yadlin, Stefan Kubicek, et al. “Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming.” Edited by Amar Abderrahmani. PLoS ONE 9, no. 4 (April 23, 2014): e95194. https://orcid.org/0000-0002-7203-4299 en_US http://dx.doi.org/10.1371/journal.pone.0095194 PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Choudhary, Amit Hu He, Kaihui Mertins, Philipp Udeshi, Namrata D. Dancik, Vlado Fomina-Yadlin, Dina Kubicek, Stefan Clemons, Paul A. Schreiber, Stuart L. Wagner, Bridget K. Carr, Steven A Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming |
| title | Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming |
| title_full | Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming |
| title_fullStr | Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming |
| title_full_unstemmed | Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming |
| title_short | Quantitative-Proteomic Comparison of Alpha and Beta Cells to Uncover Novel Targets for Lineage Reprogramming |
| title_sort | quantitative proteomic comparison of alpha and beta cells to uncover novel targets for lineage reprogramming |
| url | http://hdl.handle.net/1721.1/88043 https://orcid.org/0000-0002-7203-4299 |
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