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 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.

Tspan2: a tetraspanin protein involved in oligodendrogenesis and cancer metastasis

“…At high glucose concentrations, Tspan2 appeared to induce apoptosis of a human pancreatic β-cell line by modulating the JNK/β-catenin signalling pathway, suggesting a potential therapeutic approach against the glucotoxic apoptosis in diabetes [95]. The TSPAN2 gene locus has also recently been identified as a risk factor for ischaemic stroke [96].…”

Selective expression of TSPAN2 in vascular smooth muscle is independently regulated by TGF‐β1/SMAD and myocardin/serum response factor

“…TSPAN2 is a newly identified TSPAN family member that suppresses inflammation in the CNS (22), regulates cell motility in lung cancer (23), and promotes glucotoxic apoptosis in human pancreatic β cells (24). More recently, a genome‐wide association study (GWAS) identified a single‐nucleotide polymorphism (SNP) that is located in the regulatory region of TSPAN2 and is strongly associated with atherosclerosis in large arteries (25).…”

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

“…No matter what, we demonstrated that Sophoridine-induced β-catenin degradation was not depended on ubiquitin-proteasome pathway but depended on ESRRG, which enhances β-catenin degradation in an ubiquitin-proteasome independent manner [21] . Since ESRRG is a downstream signaling protein of MAPK pathways and the activation of MAPKs ERK1/2, p38 and JNK1/2 promote the phosphorylation of β-catenin [32][33][34] , Sophoridine may enhance β-catenin degradation via an MAPK/ESRRG pathway.…”