Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation
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Peer-reviewed
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Abstract
The proneural transcription factor Neurogenin3 (Ngn3) plays a critical role in pancreatic endocrine cell differentiation, although regulation of Ngn3 protein is largely unexplored. Here we demonstrate that Ngn3 protein undergoes cyclin-dependent kinase (Cdk)-mediated phosphorylation on multiple serine-proline sites. Replacing wild-type protein with a phosphomutant form of Ngn3 increases α cell generation, the earliest endocrine cell type to be formed in the developing pancreas. Moreover, un(der)phosphorylated Ngn3 maintains insulin expression in adult β cells in the presence of elevated c-Myc and enhances endocrine specification during ductal reprogramming. Mechanistically, preventing multi-site phosphorylation enhances both Ngn3 stability and DNA binding, promoting the increased expression of target genes that drive differentiation. Therefore, multi-site phosphorylation of Ngn3 controls its ability to promote pancreatic endocrine differentiation and to maintain β cell function in the presence of pro-proliferation cues and could be manipulated to promote and maintain endocrine differentiation in vitro and in vivo.
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1878-1551
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Leukaemia & Lymphoma Research (12029)
MRC (MR/K50127X/1)
Cancer Research UK (C14303/A17197)
Cancer Research UK (CB4230)
Wellcome Trust (103805/Z/14/Z)
Medical Research Council (MR/L021129/1)
Medical Research Council (MC_PC_12009)
Wellcome Trust (097922/Z/11/Z)
Wellcome Trust (098357/Z/12/Z)
Medical Research Council (MR/M008975/1)
Cancer Research UK (19013)
Cancer Research Uk (None)
Cancer Research UK (22585)
Cancer Research UK (17044)