PAK1, also known as p21-Activated Kinase 1, is a serine/threonine-protein kinase. It is an effector protein of small G proteins Rac and Cdc42, and plays a crucial role in regulating various cellular processes such as muscle contraction, neutrophil chemotaxis, neuronal polarization, and endothelial barrier function. PAK1 is involved in multiple signal transduction pathways and has been associated with many oncogenic signaling pathways [1,6,7].

PAK1 has been found to be frequently dysregulated in cancers, neurological disorders, and is also associated with cardiotoxicity, fibrosis, and Down syndrome [1-5]. In melanoma, PAK1 may decrease cell sensitivity to programmed cell death, promote growth-promoting molecular pathways, and create an immunosuppressive tumor microenvironment, and its inhibition can enhance anti-melanoma regimens [2]. In glioblastoma, hypoxia-induced acetylation of PAK1 enhances autophagy and promotes tumorigenesis by phosphorylating ATG5, and silencing PAK1 can block autophagy and tumor growth [3]. In Down syndrome, the enhanced activity of the DSCAM/PAK1 pathway affects neurogenesis, and its suppression can reverse the neurogenesis deficits [4]. In fibrosis, PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization, and loss of PAK1-dependent signaling can improve fibrosis [5].

In conclusion, PAK1 is a key regulator in multiple biological processes. Studies using genetic models like potential KO/CKO mouse models (not specifically detailed in the references but inferred from the research on PAK1 function) would likely further clarify its role. PAK1's dysregulation is linked to various diseases, making it a potential therapeutic target in areas such as cancer, neurological disorders, cardiotoxicity, and fibrosis [1-7].

References:

1. Semenova, Galina, Chernoff, Jonathan. . Targeting PAK1. In Biochemical Society transactions, 45, 79-88. doi:10.1042/BST20160134. https://pubmed.ncbi.nlm.nih.gov/28202661/

2. Kichina, Julia V, Maslov, Alexei, Kandel, Eugene S. 2023. PAK1 and Therapy Resistance in Melanoma. In Cells, 12, . doi:10.3390/cells12192373. https://pubmed.ncbi.nlm.nih.gov/37830586/

3. Feng, Xing, Zhang, Heng, Meng, Lingbing, Liu, Xing, Zhang, Zhiyong. 2020. Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5. In Autophagy, 17, 723-742. doi:10.1080/15548627.2020.1731266. https://pubmed.ncbi.nlm.nih.gov/32186433/

4. Tang, Xiao-Yan, Xu, Lei, Wang, Jingshen, Lin, Mingyan, Liu, Yan. . DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome. In The Journal of clinical investigation, 131, . doi:10.1172/JCI135763. https://pubmed.ncbi.nlm.nih.gov/33945512/

5. Jokl, Elliot, Mullan, Aoibheann F, Simpson, Kara, Hanley, Neil A, Piper Hanley, Karen. 2023. PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis. In Cell reports, 42, 113414. doi:10.1016/j.celrep.2023.113414. https://pubmed.ncbi.nlm.nih.gov/37967011/

6. Mirzaiebadizi, Amin, Shafabakhsh, Rana, Ahmadian, Mohammad Reza. 2025. Modulating PAK1: Accessory Proteins as Promising Therapeutic Targets. In Biomolecules, 15, . doi:10.3390/biom15020242. https://pubmed.ncbi.nlm.nih.gov/40001545/

7. Kichina, Julia V, Goc, Anna, Al-Husein, Belal, Somanath, Payaningal R, Kandel, Eugene S. . PAK1 as a therapeutic target. In Expert opinion on therapeutic targets, 14, 703-25. doi:10.1517/14728222.2010.492779. https://pubmed.ncbi.nlm.nih.gov/20507214/