SAD-A kinase controls islet β-cell size and function as a mediator of mTORC1 signaling

Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13857-62. doi: 10.1073/pnas.1307698110. Epub 2013 Aug 6.


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.

Keywords: AMPK; GLP1; LKB1; incretin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Size
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology*
  • Islets of Langerhans / cytology*
  • Luciferases
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction / physiology*
  • Statistics, Nonparametric
  • TOR Serine-Threonine Kinases / metabolism*


  • Multiprotein Complexes
  • Luciferases
  • Brsk2 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases