Kbtbd2, Kelch repeat and BTB (POZ) domain-containing 2, is a gene encoding a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. It is crucial in metabolic regulation, especially in adipocytes, and also plays roles in multiple biological processes and diseases. It is involved in pathways like insulin-like growth factor 1 (IGF-1) signaling, epidermal growth factor receptor (EGFR) signaling, and insulin signaling [1,2,5].

Conditional knockout of Kbtbd2 in embryonic osteochondroprogenitor cells or osteoblasts leads to impaired osteogenic differentiation, reduced skeletal growth and mineralization. This is due to the accumulation of p85α, which inhibits IGF-1-induced AKT activation [1]. In adipocyte-specific Kbtbd2 knockout mice, there is insulin resistance, lipodystrophy, and moderate hyperglycemia, while liver-or muscle-specific knockout mice show no such abnormalities [3]. In a mouse hepatocellular carcinoma model, overexpression of Kbtbd2 in an immortalized mouse NK cell line reduces cell proliferation, Ly49 receptor expression, and cytotoxic activity, along with down-regulation of mTOR and Erk1/2 phosphorylation [4].

In summary, Kbtbd2 is essential in regulating metabolic processes, bone development, and immune cell function. Gene knockout models, especially in mice, have been instrumental in revealing its role in conditions such as insulin resistance, diabetes, growth retardation, and cancer-related processes, highlighting its potential as a therapeutic target for these diseases [1,3,4,5].

References:

1. Xun, Yu, Jiang, Yiao, Khalid, Aysha, Rios, Jonathan, Zhang, Zhao. 2024. KBTBD2 controls bone development by regulating IGF-1 signaling during osteoblast differentiation. In Cell death and differentiation, , . doi:10.1038/s41418-024-01416-0. https://pubmed.ncbi.nlm.nih.gov/39562829/

2. Ding, Jishuang, Gao, Wei, Yang, Haiying, Wang, Longgang, Chai, Jie. 2024. KBTBD2 promotes proliferation and migration of gastric cancer via activating EGFR signaling pathway. In Pathology, research and practice, 254, 155095. doi:10.1016/j.prp.2024.155095. https://pubmed.ncbi.nlm.nih.gov/38237399/

3. Zhang, Zhao, Gallagher, Thomas, Scherer, Philipp E, Beutler, Bruce. 2020. Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome. In Proceedings of the National Academy of Sciences of the United States of America, 117, 11829-11835. doi:10.1073/pnas.2000118117. https://pubmed.ncbi.nlm.nih.gov/32381739/

4. Dai, Kai, Huang, Yabing, Chen, Zubing, Yang, Lihua, Jiang, Yingan. 2018. Kbtbd2 inhibits the cytotoxic activity of immortalized NK cells through down-regulating mTOR signaling in a mouse hepatocellular carcinoma model. In European journal of immunology, 48, 683-695. doi:10.1002/eji.201747281. https://pubmed.ncbi.nlm.nih.gov/29331106/

5. Zhang, Zhao, Turer, Emre, Li, Xiaohong, Moresco, Eva Marie Y, Beutler, Bruce. 2016. Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. In Proceedings of the National Academy of Sciences of the United States of America, 113, E6418-E6426. doi:. https://pubmed.ncbi.nlm.nih.gov/27708159/