Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells

In Hu Hwang, Junsoo Park, Jung Min Kim, Seung Il Kim, Jong Soon Choi, Kyung Bok Lee, Sung Ho Yun, Min Goo Lee, Soo Jung Park, Ik Soon Jang

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Abstract

Diabetes mellitus is a complex and heterogeneous disease, which has β-cell dysfunction at its core. Glucotoxicity affects pancreatic islets, causing β-cell apoptosis. However, the role of JNK/β-catenin signaling in glucotoxic β-cell apoptosis is not well understood. Recently, we identified tetraspanin-2 (TSPAN2) protein as a proapoptotic β-cell factor induced by glucose, suggesting that TSPAN2 might contribute to pancreatic β-cell glucotoxicity. To investigate the effects of glucose concentration on TSPAN2 expression and apoptosis, we used reverted immortalizedRNAKT-15 human pancreatic β cells.High TSPAN2 levels up-regulated phosphorylated (p) JNK and induced apoptosis. p-JNK enhanced the phosphorylation of b-catenin and Dickkopf-1 (Dkk1). Dkk1 knockdownbysmall interfering (si)RNAup-regulated nuclearb-catenin, suggestingthat it isaJNK/β-catenin-dependent pathway. siRNA-mediatedTSPAN2depletion inRNAKT-15 cells increased nuclearb-catenin.ThisdecreasedBCL2- associated X protein (Bax) activation, leading to marked protection against high glucose-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Thus, TSPAN2might have induced Bax translocation and caspase-3 activation in pancreatic β cells, thereby promoting the apoptosis ofRNAKT-15 cells by regulating the JNK/ b-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-inducedβ-cell failure.-Hwang, I.-H., Park, J., Kim,J.M., Kim,S. I.,Choi, J.-S.,Lee, K.-B., Yun, S. H., Lee, M.-G., Park, S. J., Jang, I.-S. Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells.

Original languageEnglish
Pages (from-to)3107-3116
Number of pages10
JournalFASEB Journal
Volume30
Issue number9
DOIs
Publication statusPublished - 2016 Sep

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All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Hwang, I. H., Park, J., Kim, J. M., Il Kim, S., Choi, J. S., Lee, K. B., Yun, S. H., Lee, M. G., Park, S. J., & Jang, I. S. (2016). Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells. FASEB Journal, 30(9), 3107-3116. https://doi.org/10.1096/fj.201600240RR