Silencing the G-protein coupled receptor 3-salt inducible kinase 2 pathway promotes human β cell proliferation

Autor: Robert A. Screaton, Tatsuya Kin, Jillian L Rourke, Jun-Ichi Sakamaki, Emily Moon, Caterina Iorio, Queenie Hu, Lisa Wells
Rok vydání: 2021
Předmět:
Zdroj: Communications Biology
Communications Biology, Vol 4, Iss 1, Pp 1-13 (2021)
ISSN: 2399-3642
Popis: Loss of pancreatic β cells is the hallmark of type 1 diabetes, for which provision of insulin is the standard of care. While regenerative and stem cell therapies hold the promise of generating single-source or host-matched tissue to obviate immune-mediated complications, these will still require surgical intervention and immunosuppression. Here we report the development of a high-throughput RNAi screening approach to identify upstream pathways that regulate adult human β cell quiescence and demonstrate in a screen of the GPCRome that silencing G-protein coupled receptor 3 (GPR3) leads to human pancreatic β cell proliferation. Loss of GPR3 leads to activation of Salt Inducible Kinase 2 (SIK2), which is necessary and sufficient to drive cell cycle entry, increase β cell mass, and enhance insulin secretion in mice. Taken together, our data show that targeting the GPR3-SIK2 pathway is a potential strategy to stimulate the regeneration of β cells.
Caterina Iorio et al. use a high-throughput RNAi screen to identify the GPR3-SIK2-CDKN1B axis as key players involved in regulating pancreatic beta cell proliferation. These results suggest that GPR3 and SIK2 are both potential targets to stimulate regeneration of beta cells in diseases like type 1 diabetes.
Databáze: OpenAIRE
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