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

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2016 Sep

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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 immortalized RNAKT-15 human pancreatic β cells. High TSPAN2 levels up-regulated phosphorylated (p) JNK and induced apoptosis. p-JNK enhanced the phosphorylation of β-catenin and Dickkopf-1 (Dkk1). Dkk1 knockdown by small interfering (si)RNA up-regulated nuclear β-catenin, suggesting that it is a JNK/β-catenin-dependent pathway. siRNA-mediated TSPAN2 depletion in RNAKT-15 cells increased nuclear β-catenin. This decreased BCL2-associated X protein (Bax) activation, leading to marked protection against high glucose-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Thus, TSPAN2 might have induced Bax translocation and caspase-3 activation in pancreatic β cells, thereby promoting the apoptosis of RNAKT-15 cells by regulating the JNK/β-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-induced β-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. © The Author(s).

Citation

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. Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2016 Sep;30(9):3107-16