Salt-Inducible Kinase 1 Terminates cAMP Signaling by an Evolutionarily Conserved Negative-Feedback Loop in β-Cells.
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.
Division of Life Sciences, Korea University, Seoul, Republic of Korea.
Min-Jung
MJ
Kim
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Su-Kyung
SK
Park
Division of Life Sciences, Korea University, Seoul, Republic of Korea.
Ji-Hyun
JH
Lee
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Chang-Yun
CY
Jung
Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea Division of Sports Science, College of Science and Technology, Konkuk University, Chungju, Republic of Korea.
Dong Jun
DJ
Sung
Department of Physiology and Obesity-Mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Republic of Korea.
Jae-Hyung
JH
Park
Division of Life Sciences, Korea University, Seoul, Republic of Korea.
Young-Sil
YS
Yoon
Division of Life Sciences, Korea University, Seoul, Republic of Korea Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Jinyoung
J
Park
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Keun-Gyu
KG
Park
Department of Physiology and Obesity-Mediated Disease Research Center, Keimyung University School of Medicine, Daegu, Republic of Korea.
Dae-Kyu
DK
Song
Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Hana
H
Cho
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea koohoi@korea.ac.kr stkim@skku.edu.
Seong-Tae
ST
Kim
Division of Life Sciences, Korea University, Seoul, Republic of Korea koohoi@korea.ac.kr stkim@skku.edu.
Seung-Hoi
SH
Koo
D000818:Animals; D005075:Biological Evolution; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D025461:Feedback, Physiological; D005947:Glucose / Q000378:metabolism*; D057895:Haploinsufficiency; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D007328:Insulin; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; C495376:Sik1 protein, mouse; C120299:Sik1 protein, rat; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C531980:PDE4D protein, mouse; C528468:PDE4D protein, rat; D005947:Glucose