Salt-Inducible Kinase 1 Terminates cAMP Signaling by an Evolutionarily Conserved Negative-Feedback Loop in β-Cells

Min Jung Kim, Su Kyung Park, Ji Hyun Lee, Chang Yun Jung, Dong J un Sung, Jae Hyung Park, Young Sil Yoon, Jinyoung Park, Keun Gyu Park, Dae Kyu Song, Hana Cho, Seong Tae Kim, Seung-Hoi Koo

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20 Citations (Scopus)

Abstract

Pancreatic β-cells are critical in the regulation of glucose homeostasis by controlled secretion of insulin in mammals. Activation of protein kinase A by cAMP is shown to be responsible for enhancing this pathway, which is countered by phosphodiesterase (PDE) that converts cAMP to AMP and turns off the signal. Salt-inducible kinases (SIKs) were also known to inhibit cAMP signaling, mostly by promoting inhibitory phosphorylation on CREB-regulated transcription coactivators. Here, we showed that SIK1 regulates insulin secretion in β-cells by modulating PDE4D and cAMP concentrations. Haploinsufficiency of SIK1 led to the improved glucose tolerance due to the increased glucose-stimulated insulin secretion. Depletion of SIK1 promoted higher cAMP concentration and increased insulin secretion from primary islets, suggesting that SIK1 controls insulin secretion through the regulation of cAMP signaling. By using a consensus phosphorylation site of SIK1, we identified PDE4D as a new substrate for this kinase family. In vitro kinase assay as well as mass spectrometry analysis revealed that the predicted Ser(136) and the adjacent Ser(141) of PDE4D are critical in SIK1-mediated phosphorylation. We found that overexpression of either SIK1 or PDE4D in β-cells reduced insulin secretion, while inhibition of PDE4 activity by rolipram or knockdown of PDE4D restored it, showing indeed that SIK1-dependent phosphorylation of PDE4D is critical in reducing cAMP concentration and insulin secretion from β-cells. Taken together, we propose that SIK1 serves as a part of a self-regulatory circuit to modulate insulin secretion from pancreatic β-cells by controlling cAMP concentration through modulation of PDE4D activity.

Original languageEnglish
Pages (from-to)3189-3202
Number of pages14
JournalDiabetes
Volume64
Issue number9
DOIs
Publication statusPublished - 2015 Sep 1

ASJC Scopus subject areas

  • Medicine(all)

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    Kim, M. J., Park, S. K., Lee, J. H., Jung, C. Y., Sung, D. J. U., Park, J. H., Yoon, Y. S., Park, J., Park, K. G., Song, D. K., Cho, H., Kim, S. T., & Koo, S-H. (2015). Salt-Inducible Kinase 1 Terminates cAMP Signaling by an Evolutionarily Conserved Negative-Feedback Loop in β-Cells. Diabetes, 64(9), 3189-3202. https://doi.org/10.2337/db14-1240