MARK2, short for Microtubule Affinity-Regulating Kinase 2, is a serine/threonine protein kinase. It phosphorylates microtubule-associated proteins and is crucial in cancer and neurodegenerative diseases, regulating multiple signaling pathways like WNT, PI3K/AKT/mTOR (PAM), and NF-κB [3].

In functional studies, MARK2 loss-of-function (LoF) variants predominate (81%) in individuals with autism spectrum disorder (ASD) and other neurodevelopmental disorders. Using proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs), MARK2 loss led to early neuronal developmental and functional deficits, including abnormal neural rosette polarity and neural progenitor cell proliferation/differentiation imbalance. Mark2+/- mice showed abnormal cortical formation and ASD-like behavior, linking MARK2 loss to down-regulation of the WNT/β-catenin signaling pathway [1]. In cancer research, MARK2 is an absolute catalytic requirement for YAP/TAZ function in diverse carcinomas and sarcomas. Targeting MARK2/3 can reactivate the Hippo tumor-suppressive pathway [2].

In conclusion, MARK2 is essential in regulating multiple biological processes. Gene knockout models, such as the Mark2+/- mice, have revealed its significant roles in neurodevelopmental disorders like ASD and in cancer. These findings contribute to understanding the mechanisms of these diseases and may provide potential therapeutic targets for treatment.

References:

1. Gong, Maolei, Li, Jiayi, Qin, Zailong, Liu, Chang-Mei, Chen, Xiaoli. 2024. MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway. In American journal of human genetics, 111, 2392-2410. doi:10.1016/j.ajhg.2024.09.006. https://pubmed.ncbi.nlm.nih.gov/39419027/

2. Klingbeil, Olaf, Skopelitis, Damianos, Tonelli, Claudia, Cifani, Paolo, Vakoc, Christopher R. . MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer. In Cancer discovery, 14, 2471-2488. doi:10.1158/2159-8290.CD-23-1529. https://pubmed.ncbi.nlm.nih.gov/39058094/

3. Lei, Yining, Zhang, Ruyi, Cai, Fei. 2024. Role of MARK2 in the nervous system and cancer. In Cancer gene therapy, 31, 497-506. doi:10.1038/s41417-024-00737-z. https://pubmed.ncbi.nlm.nih.gov/38302729/