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Mol Cell Endocrinol. 2017 Oct 15;454:146-157. doi: 10.1016/j.mce.2017.06.020. Epub 2017 Jun 22.

Nuclear import of glucokinase in pancreatic beta-cells is mediated by a nuclear localization signal and modulated by SUMOylation.

Author information

1
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
2
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
3
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.
4
Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School and Harvard Stem Cell Institute, Boston, MA, USA; Department of Endocrinology and Metabolism, Yokohama City University, Yokohama, Japan.
5
Lund University Diabetes Centre, Malmö, Sweden.
6
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.
7
Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School and Harvard Stem Cell Institute, Boston, MA, USA.
8
Proteomics Unit (PROBE), Department of Biomedicine, University of Bergen, Norway.
9
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
10
Department of Biomedicine, University of Bergen, Bergen, Norway.
11
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway; Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
12
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Biomedical Laboratory Sciences and Chemical Engineering, Western Norway University of Applied Sciences, Bergen, Norway. Electronic address: Lise.Bjorkhaug.Gundersen@hvl.no.

Abstract

The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal (30LKKVMRR36) in the human enzyme. Substituting the residues KK31,32 and RR35,36 with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell.

KEYWORDS:

Beta-cells; Glucokinase; Human islets; MIN6 cells; Nuclear localization signal; Pancreatic islets; SUMOylation

PMID:
28648619
DOI:
10.1016/j.mce.2017.06.020
[Indexed for MEDLINE]

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