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

Jia Nie, Xiaolei Liu, Brendan N. Lilley, Hai Zhang, Yu Chin Albert Pan, Scot R. Kimball, Jun Zhang, Weiping Zhang, Li Wang, Leonard S. Jefferson, Joshua R. Sanes, Xiao Han, Yuguang Shi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 SADA 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.

Original languageEnglish (US)
Pages (from-to)13857-13862
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number34
DOIs
StatePublished - Aug 28 2013

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Mediator Complex
Islets of Langerhans
Cell Size
Synapses
Phosphotransferases
Pancreas
Sirolimus
Protein Kinases
TOR Serine-Threonine Kinases
Ribosomal Protein S6 Kinases
Glucose
Insulinoma
5' Untranslated Regions
Protein Biosynthesis
Adenosine Monophosphate
Insulin
Cell Line
Messenger RNA

Keywords

  • AMPK
  • GLP1
  • Incretin
  • LKB1

ASJC Scopus subject areas

  • General

Cite this

SAD-A kinase controls islet β-cell size and function as a mediator of mTORC1 signaling. / Nie, Jia; Liu, Xiaolei; Lilley, Brendan N.; Zhang, Hai; Pan, Yu Chin Albert; Kimball, Scot R.; Zhang, Jun; Zhang, Weiping; Wang, Li; Jefferson, Leonard S.; Sanes, Joshua R.; Han, Xiao; Shi, Yuguang.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 34, 28.08.2013, p. 13857-13862.

Research output: Contribution to journalArticle

Nie, J, Liu, X, Lilley, BN, Zhang, H, Pan, YCA, Kimball, SR, Zhang, J, Zhang, W, Wang, L, Jefferson, LS, Sanes, JR, Han, X & Shi, Y 2013, 'SAD-A kinase controls islet β-cell size and function as a mediator of mTORC1 signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 34, pp. 13857-13862. https://doi.org/10.1073/pnas.1307698110
Nie, Jia ; Liu, Xiaolei ; Lilley, Brendan N. ; Zhang, Hai ; Pan, Yu Chin Albert ; Kimball, Scot R. ; Zhang, Jun ; Zhang, Weiping ; Wang, Li ; Jefferson, Leonard S. ; Sanes, Joshua R. ; Han, Xiao ; Shi, Yuguang. / SAD-A kinase controls islet β-cell size and function as a mediator of mTORC1 signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 34. pp. 13857-13862.
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