MARK1, also known as microtubule affinity regulating kinase 1, is involved in various biological processes. It has been implicated in neurodevelopmental disorders, and its accelerated evolution in the human lineage suggests a role in cognition. Structurally, its kinase associated-1 (KA1) domain can auto-inhibit the kinase activity [5].

Forebrain-specific conditional knockout (cKO) of Mark1 in mice reveals its crucial in vivo roles. The cKO mice exhibit defects in dendritic spine morphogenesis in hippocampal CA1 pyramidal neurons, with a significant reduction in spine density. This is accompanied by synaptic accumulation of GKAP and GluA2 (or GluR2), and the mice show deficits in spatial learning in the Morris water maze and reduced anxiety-like behaviors, indicating its role in cognitive functions [1,2]. In lung development, Mark1-knockout (KO) mice have impaired distal sacculation and type I pneumocyte (AECI) flattening. Fibroblasts expressing Mark1 are required for the terminal stages of pulmonary development, as Mark1-mediated fibroblast activation induces AECI flattening [3]. In hepatocellular carcinoma (HCC), MARK1 expression is decreased in HCC tissues and cells. Overexpressing MARK1 suppresses sorafenib-induced proliferation in resistant cells, as it potentially restrains HCC progression and enhances sorafenib resistance by negatively modulating POTEE expression [4].

In conclusion, MARK1 plays essential roles in multiple biological processes. Mouse KO/CKO models have been instrumental in revealing its functions in the nervous system, lung development, and cancer. In the nervous system, it regulates dendritic spine morphogenesis and cognitive functions. In the lung, it is crucial for distal airspace expansion. In HCC, it affects cancer progression and drug resistance, providing potential therapeutic targets for related diseases.

References:

1. Kelly-Castro, Emily C, Shear, Rebecca, Dindigal, Ankitha H, Bhagwat, Maitreyee, Zhang, Huaye. 2024. MARK1 regulates dendritic spine morphogenesis and cognitive functions in vivo. In Experimental neurology, 376, 114752. doi:10.1016/j.expneurol.2024.114752. https://pubmed.ncbi.nlm.nih.gov/38484863/

2. Kelly-Castro, Emily C, Shear, Rebecca, Dindigal, Ankitha H, Bhagwat, Maitreyee, Zhang, Huaye. 2023. MARK1 regulates dendritic spine morphogenesis and cognitive functions in vivo. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.12.03.569757. https://pubmed.ncbi.nlm.nih.gov/38105977/

3. Fumoto, Katsumi, Takigawa-Imamura, Hisako, Sumiyama, Kenta, Maehara, Natsumi, Kikuchi, Akira. 2019. Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development. In Journal of cell science, 132, . doi:10.1242/jcs.235556. https://pubmed.ncbi.nlm.nih.gov/31719161/

4. Lu, Xin, Chen, Zhiyuan, Mi, Wenting, Zheng, Jianming, Liu, Yubin. 2024. MARK1 suppress malignant progression of hepatocellular carcinoma and improves sorafenib resistance through negatively regulating POTEE. In Open medicine (Warsaw, Poland), 19, 20241060. doi:10.1515/med-2024-1060. https://pubmed.ncbi.nlm.nih.gov/39534429/

5. Emptage, Ryan P, Lemmon, Mark A, Ferguson, Kathryn M, Marmorstein, Ronen. 2018. Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain. In Structure (London, England : 1993), 26, 1137-1143.e3. doi:10.1016/j.str.2018.05.008. https://pubmed.ncbi.nlm.nih.gov/30099988/