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

ABSTRACT Diabetes mellitus is a complex and heterogeneous disease, which has b‐cell dysfunction at its core. Glucotoxicity affects pancreatic islets, causing b‐cell apoptosis. However, the role of JNK/β‐catenin signaling in glucotoxic b‐cell apoptosis is not well understood. Recently, we identified tetraspanin‐2 (TSPAN2) protein as a proapoptotic b‐cell factor induced by glucose, suggesting that TSPAN2 might contribute to pancreatic b‐cell glucotoxicity. To investigate the effects of glucose concentration on TSPAN2 expression and apoptosis, we used reverted immortalized RNAKT‐15 human pancreatic b 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 BCL2associated 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 b 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 b‐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. FASEB J. 30, 3107–3116 (2016). www.fasebj.org