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

ABSTRACT: The mammalian target of rapamycin (mTOR) plays an important role in controlling islet ?-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 ?-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 ?-cell size, whereas SAD-A overexpression significantly increased the size of mouse insulinomas cell lines ?-cells. In direct support of SAD-A as a unique mediator of mTORC1 signaling in islet ?-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.

SUBMITTER: Nie J 

PROVIDER: S-EPMC3752253 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature