Wdr24-KO Mouse

Wdr24 is an essential component of the GATOR2 complex. The GATOR2 complex is crucial in the nutrient-sensing machinery, specifically in linking amino acid signals to mTORC1, a central regulator of metabolism and cell growth [2,3,4,5,6]. It also has a role in the glucose-sensing capability of mTORC1 [3].

In gene knockout studies, Wdr24 ablation in mice leads to severe growth defects and embryonic lethality at E10.5, preventing mTORC1 activation, which reveals its essentiality during embryonic development [4]. Phosphomimetic Wdr24S155D knock-in mice exhibit early embryonic lethality and reduced mTORC1 activity, while phospho-deficient Wdr24S155A knock-in mice are more resistant to fasting and display elevated mTORC1 activity, indicating the role of AMPK-mediated phosphorylation of Wdr24 in modulating glucose-induced mTORC1 activation [3]. In Drosophila, Wdr24 is a critical effector of the GATOR2 complex, promoting TORC1 activation and cellular growth, and also has a TORC1-independent role in regulating lysosome dynamics and autophagic flux [7].

In conclusion, Wdr24 is key for mTORC1 activation in response to amino acids and glucose, playing a vital role in embryonic development and cellular metabolism. Mouse models, including gene knockouts and knock-ins, have been instrumental in revealing its functions, with implications for understanding diseases related to abnormal mTORC1 signaling, such as cancer [1,3,4,6].

References:

1. Yin, Shasha, Liu, Liu, Ball, Lauren E, Wang, Haizhen, Gan, Wenjian. 2023. CDK5-PRMT1-WDR24 signaling cascade promotes mTORC1 signaling and tumor growth. In Cell reports, 42, 112316. doi:10.1016/j.celrep.2023.112316. https://pubmed.ncbi.nlm.nih.gov/36995937/

2. Valenstein, Max L, Rogala, Kacper B, Lalgudi, Pranav V, Quast, Jan-Philipp, Sabatini, David M. 2022. Structure of the nutrient-sensing hub GATOR2. In Nature, 607, 610-616. doi:10.1038/s41586-022-04939-z. https://pubmed.ncbi.nlm.nih.gov/35831510/

3. Dai, Xiaoming, Jiang, Cong, Jiang, Qiwei, Guo, Jianping, Wei, Wenyi. 2023. AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation. In Nature metabolism, 5, 265-276. doi:10.1038/s42255-022-00732-4. https://pubmed.ncbi.nlm.nih.gov/36732624/

4. Jiang, Cong, Dai, Xiaoming, He, Shaohui, Xiao, Jianru, Wei, Wenyi. 2022. Ring domains are essential for GATOR2-dependent mTORC1 activation. In Molecular cell, 83, 74-89.e9. doi:10.1016/j.molcel.2022.11.021. https://pubmed.ncbi.nlm.nih.gov/36528027/

5. Bar-Peled, Liron, Chantranupong, Lynne, Cherniack, Andrew D, Meyerson, Matthew, Sabatini, David M. . A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. In Science (New York, N.Y.), 340, 1100-6. doi:10.1126/science.1232044. https://pubmed.ncbi.nlm.nih.gov/23723238/

6. Solanki, Sumeet, Sanchez, Katherine, Ponnusamy, Varun, Lee, Jun Hee, Shah, Yatrik M. 2022. Dysregulated Amino Acid Sensing Drives Colorectal Cancer Growth and Metabolic Reprogramming Leading to Chemoresistance. In Gastroenterology, 164, 376-391.e13. doi:10.1053/j.gastro.2022.11.014. https://pubmed.ncbi.nlm.nih.gov/36410445/

7. Cai, Weili, Wei, Youheng, Jarnik, Michal, Reich, John, Lilly, Mary A. 2016. The GATOR2 Component Wdr24 Regulates TORC1 Activity and Lysosome Function. In PLoS genetics, 12, e1006036. doi:10.1371/journal.pgen.1006036. https://pubmed.ncbi.nlm.nih.gov/27166823/