SAD-A kinase controls islet β-cell size and function as a mediator of mTORC1 signaling.
The mammalian target of rapamycin (mTOR) plays an important role in controlling islet β-cell function. However, the underlying molecular mechanisms remain poorly elucidated. Synapses of amphids defective kinase-A (SAD-A) is a 5' adenosine monophosphate-activated protein kinase-related protein kinase that is exclusively expressed in pancreas and brain. In this study, we investigated a role of the kinase in regulating pancreatic β-cell morphology and function as a mediator of mTOR complex 1 (mTORC1) signaling. We show that global SAD-A deletion leads to defective glucose-stimulated insulin secretion and petite islets, which are reminiscent of the defects in mice with global deletion of ribosomal protein S6 kinase 1, a downstream target of mTORC1. Consistent with these findings, selective deletion of SAD-A in pancreas decreased islet β-cell size, whereas SAD-A overexpression significantly increased the size of mouse insulinomas cell lines β-cells. In direct support of SAD-A as a unique mediator of mTORC1 signaling in islet β-cells, we demonstrate that glucose dramatically stimulated SAD-A protein translation in isolated mouse islets, which was potently inhibited by rapamycin, an inhibitor of mTORC1. Moreover, the 5'-untranslated region of SAD-A mRNA is highly structured and requires mTORC1 signaling for its translation initiation. Together, these findings identified SAD-A as a unique pancreas-specific effector protein of mTORC1 signaling.
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 210029, China.
Jia
J
Nie
Xiaolei
X
Liu
Brendan N
BN
Lilley
Hai
H
Zhang
Y Albert
YA
Pan
Scot R
SR
Kimball
Jun
J
Zhang
Weiping
W
Zhang
Li
L
Wang
Leonard S
LS
Jefferson
Joshua R
JR
Sanes
Xiao
X
Han
Yuguang
Y
Shi
D000818:Animals; D045744:Cell Line, Tumor; D048429:Cell Size; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology*; D008156:Luciferases; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D046912:Multiprotein Complexes; D008156:Luciferases; C496825:Brsk2 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
AMPK; GLP1; LKB1; incretin