SAD-A kinase controls islet ß-cell size and function as a mediator of mTORC1 signaling.
Proc Natl Acad Sci U S A
; 110(34): 13857-62, 2013 Aug 20.
Article
in En
| MEDLINE
| ID: mdl-23922392
ABSTRACT
The mammalian target of rapamycin (mTOR) plays an important role in controlling islet ß-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 ß-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 ß-cell size, whereas SAD-A overexpression significantly increased the size of mouse insulinomas cell lines ß-cells. In direct support of SAD-A as a unique mediator of mTORC1 signaling in islet ß-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 words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Islets of Langerhans
/
Protein Serine-Threonine Kinases
/
Multiprotein Complexes
/
Insulin-Secreting Cells
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TOR Serine-Threonine Kinases
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2013
Document type:
Article
Affiliation country: