KCTD20, also known as potassium channel tetramerization protein domain containing 20, is a positive regulator of Akt [2]. It binds to all Akt isoforms and protein phosphatase 2A (PP2A), inhibiting PP2A-mediated dephosphorylation of Akt and thus keeping Akt activated. KCTD20 is ubiquitously expressed in both non-nervous and nervous tissues and may play a role in regulating cell death and growth [2]. It is also predicted to participate in the AKT-mTOR-p70 S6k signaling cascade [6].

In tauopathy, suppression of KCTD20 potently ameliorates tau pathology and neurodegeneration in glutamate-treated induced pluripotent stem cell (iPSC)-derived cerebral organoids and mice, as well as in transgenic mice overexpressing mutant human tau. KCTD20 suppression reduces oligomeric tau and improves neuron survival by activating lysosomal exocytosis, which clears pathological tau [1]. In non-small cell lung cancer (NSCLC), KCTD20 promotes cell proliferation and invasion through enhancing Fak (Tyr397) and Akt (Thr 308) phosphorylation, and its high expression is associated with advanced TNM stage, positive lymph node metastasis, and poor overall survival [3]. In SK-N-SH cells treated with MPP + (related to Parkinson's disease), miR-423-5p overexpression mitigates cell injury by down-regulating KCTD20 [4]. In glioma, the lncRNA NEAT1 upregulates KCTD20 expression by competitively binding to miR-324-5p, affecting cell proliferation and apoptosis [5].

In conclusion, KCTD20 is an important regulator in multiple biological processes, especially in the Akt-related signaling pathway. Studies using mouse models and cell lines have revealed its roles in neurodegenerative diseases like tauopathy and Parkinson's disease, as well as in cancers such as NSCLC and glioma. Understanding KCTD20's functions provides insights into the mechanisms of these diseases and may offer potential therapeutic targets.

References:

1. Berlind, Joshua E, Lai, Jesse D, Lie, Cecilia, Yu, Violeta, Ichida, Justin K. 2025. KCTD20 suppression mitigates excitotoxicity in tauopathy patient organoids. In Neuron, 113, 1169-1189.e7. doi:10.1016/j.neuron.2025.02.001. https://pubmed.ncbi.nlm.nih.gov/40049159/

2. Nawa, Mikiro, Matsuoka, Masaaki. 2013. KCTD20, a relative of BTBD10, is a positive regulator of Akt. In BMC biochemistry, 14, 27. doi:10.1186/1471-2091-14-27. https://pubmed.ncbi.nlm.nih.gov/24156551/

3. Zhang, Xiupeng, Zhou, Haijing, Cai, Lin, Li, Qingchang, Miao, Yuan. 2017. Kctd20 promotes the development of non-small cell lung cancer through activating Fak/AKT pathway and predicts poor overall survival of patients. In Molecular carcinogenesis, 56, 2058-2065. doi:10.1002/mc.22660. https://pubmed.ncbi.nlm.nih.gov/28398603/

4. Zheng, Yanhua, Liu, Junpeng, Zhuang, Jiajun, Yu, Miao, Li, Zhihui. 2021. Silencing of UCA1 Protects Against MPP+-Induced Cytotoxicity in SK-N-SH Cells via Modulating KCTD20 Expression by Sponging miR-423-5p. In Neurochemical research, 46, 878-887. doi:10.1007/s11064-020-03214-9. https://pubmed.ncbi.nlm.nih.gov/33464446/

5. Zhang, Jiale, Li, Yangyang, Liu, Yuqi, Lu, Xiaoming, Liu, Weiping. 2021. Long non‑coding RNA NEAT1 regulates glioma cell proliferation and apoptosis by competitively binding to microRNA‑324‑5p and upregulating KCTD20 expression. In Oncology reports, 46, . doi:10.3892/or.2021.8076. https://pubmed.ncbi.nlm.nih.gov/33982764/

6. Skoblov, Mikhail, Marakhonov, Andrey, Marakasova, Ekaterina, Birerdinc, Aybike, Baranova, Ancha. 2013. Protein partners of KCTD proteins provide insights about their functional roles in cell differentiation and vertebrate development. In BioEssays : news and reviews in molecular, cellular and developmental biology, 35, 586-96. doi:10.1002/bies.201300002. https://pubmed.ncbi.nlm.nih.gov/23592240/