Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets

Tomoko Okuyama, Jun Shirakawa, Hiromi Yanagisawa, Mayu Kyohara, Shunsuke Yamazaki, Kazuki Tajima, Yu Togashi, Yasuo Terauchi

Research output: Contribution to journalArticle

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Abstract

Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time-and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets. GKA-induced Fbln5 upregulation in the islets was blunted by a glucokinase inhibitor, KATP channel opener, Ca2+ channel blocker and calcineurin inhibitor, while it was augmented by harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1 A inhibitor. Although deletion of Fbln5 in mice had no significant effects on the glucose tolerance or β-cell functions, adenovirus-mediated Fbln5 overexpression increased glucose-stimulated insulin secretion in INS-1 rat insulinoma cells. Since the islet Fbln5 expression is regulated through a glucokinase/KATP channel/calcineurin/nuclear factor of activated T cells (NFAT) pathway crucial for the maintenance of β-cell functions, further investigation of Fbln5 functions in the islets is warranted.

Original languageEnglish (US)
Article number2364
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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NFATC Transcription Factors
Glucokinase
Calcineurin
Islets of Langerhans
Proteins
Glucose
KATP Channels
Harmine
Insulin
Insulin Receptor Substrate Proteins
Insulinoma
fibulin
High Fat Diet
Adenoviridae
Up-Regulation
Maintenance
Apoptosis

ASJC Scopus subject areas

  • General

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Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets. / Okuyama, Tomoko; Shirakawa, Jun; Yanagisawa, Hiromi; Kyohara, Mayu; Yamazaki, Shunsuke; Tajima, Kazuki; Togashi, Yu; Terauchi, Yasuo.

In: Scientific Reports, Vol. 7, No. 1, 2364, 01.12.2017.

Research output: Contribution to journalArticle

Okuyama, Tomoko ; Shirakawa, Jun ; Yanagisawa, Hiromi ; Kyohara, Mayu ; Yamazaki, Shunsuke ; Tajima, Kazuki ; Togashi, Yu ; Terauchi, Yasuo. / Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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