Ulk3, short for unc-51 like kinase 3, is a serine/threonine protein kinase involved in multiple cellular processes. It plays a role in autophagy, a catabolic process for cellular homeostasis [3]. It also regulates cytokinetic abscission during cell division by phosphorylating ESCRT-III proteins [4]. Additionally, it is implicated in the Sonic hedgehog pathway [6]. Its functions have significance in processes like keratinocyte self-renewal, cancer-associated fibroblast activation, and neuronal dendritic arbor size regulation, making it relevant in the study of diseases such as cancer and Alzheimer's disease [1,2,5].

In keratinocytes and squamous cell carcinoma (SCC)-derived cells, loss of Ulk3 by gene silencing or deletion reduces proliferation and clonogenicity, and affects transcription related to stem cell-related and metabolism programs. Mechanistically, it directly binds and regulates the activity of histone arginine methyltransferases PRMT1 and PRMT5, and its loss compromises their chromatin association and histone H4 methylation. Downmodulating Ulk3 blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in skin cancer models [1]. In mouse hippocampal neurons, Bin1 knockdown leads to increased Ulk3 expression, which supports autophagosome formation. Reducing Ulk3 activity or expression mitigates the Bin1 knockdown-induced hippocampal volume loss and spatial memory decline [2].

In summary, Ulk3 is crucial for various cellular functions and disease-related processes. Its role in keratinocyte self-renewal and tumorigenesis, as well as in the context of Alzheimer's disease-related neuronal changes, is revealed through gene-silencing and knockdown studies. These findings suggest its potential as a therapeutic target in cancer and for relieving detrimental effects in Alzheimer's disease [1,2].

References:

1. Goruppi, Sandro, Clocchiatti, Andrea, Bottoni, Giulia, Simon, Christian, Paolo Dotto, G. 2023. The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome. In Nature communications, 14, 887. doi:10.1038/s41467-023-36410-6. https://pubmed.ncbi.nlm.nih.gov/36797248/

2. Jin, Yuxi, Zhao, Lin, Zhang, Yanli, Xiao, Ming, Sheng, Chengyu. 2024. BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons. In Autophagy, 21, 223-242. doi:10.1080/15548627.2024.2393932. https://pubmed.ncbi.nlm.nih.gov/39171951/

3. González-Rodríguez, Patricia, Cheray, Mathilde, Keane, Lily, Engskog-Vlachos, Pinelopi, Joseph, Bertrand. 2022. ULK3-dependent activation of GLI1 promotes DNMT3A expression upon autophagy induction. In Autophagy, 18, 2769-2780. doi:10.1080/15548627.2022.2039993. https://pubmed.ncbi.nlm.nih.gov/35226587/

4. Caballe, Anna, Wenzel, Dawn M, Agromayor, Monica, Sundquist, Wesley I, Martin-Serrano, Juan. 2015. ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins. In eLife, 4, e06547. doi:10.7554/eLife.06547. https://pubmed.ncbi.nlm.nih.gov/26011858/

5. Goruppi, Sandro, Procopio, Maria-Giuseppina, Jo, Seunghee, Neel, Victor, Dotto, G Paolo. . The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI. In Cell reports, 20, 2468-2479. doi:10.1016/j.celrep.2017.08.048. https://pubmed.ncbi.nlm.nih.gov/28877478/

6. Kasak, Lagle, Näks, Mihkel, Eek, Priit, Kasvandik, Sergo, Piirsoo, Marko. 2018. Characterization of Protein Kinase ULK3 Regulation by Phosphorylation and Inhibition by Small Molecule SU6668. In Biochemistry, 57, 5456-5465. doi:10.1021/acs.biochem.8b00356. https://pubmed.ncbi.nlm.nih.gov/30096229/