PAK3, also known as p21-activated serine/threonine kinase 3, is a serine/threonine protein kinase. It is involved in multiple cellular processes such as regulating actin cytoskeleton dynamics through pathways like the PAK3-LIMK1-cofilin axis, and is associated with the mTOR and S6K1 pathways [3]. PAK3 is crucial for normal brain development, synaptic plasticity, and has implications in cell migration, polarity, and lipid homeostasis [4,5,6,7]. Genetic models, especially mouse models, have been instrumental in studying its functions.

In obesity cardiomyopathy, cardiac-specific PAK3 overexpression in mice led to increased myocardial lipid deposition and cardiac dysfunction, as PAK3 promoted SREBP1c nuclear expression via mTOR and S6K1 activation [1]. In cranial irradiation-induced cognitive impairment in mice, down-regulation of PAK3 due to up-regulation of miR-206-3p targeting PAK3 was associated with cognitive dysfunction, and restoring PAK3 signaling via miR-206-3p antagonist improved cognition [3]. In hepatocellular carcinoma, high PAK3 expression promoted cell proliferation, migration, invasion, and regulated EMT process [2].

In conclusion, PAK3 plays essential roles in processes like lipid homeostasis in the heart, cognitive function in the brain, and cancer cell behavior. Mouse models, including overexpression and gene-knockdown models, have revealed its contribution to obesity-related cardiomyopathy, cranial irradiation-induced cognitive impairment, and hepatocellular carcinoma metastasis. These findings highlight PAK3 as a potential therapeutic target in these disease areas.

References:

1. Chen, Xinyi, Ruiz-Velasco, Andrea, Zou, Zhiyong, Müller, Oliver J, Liu, Wei. . PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy. In Diabetes, 73, 1805-1820. doi:10.2337/db24-0240. https://pubmed.ncbi.nlm.nih.gov/39137120/

2. Gao, Zhi, Zhong, Mengya, Ye, Zhijian, Zhao, Yongxiang, Zhang, Zhiyong. 2022. PAK3 promotes the metastasis of hepatocellular carcinoma by regulating EMT process. In Journal of Cancer, 13, 153-161. doi:10.7150/jca.61918. https://pubmed.ncbi.nlm.nih.gov/34976179/

3. Lee, Haksoo, Kang, Hyunkoo, Moon, Changjong, Youn, BuHyun. 2023. PAK3 downregulation induces cognitive impairment following cranial irradiation. In eLife, 12, . doi:10.7554/eLife.89221. https://pubmed.ncbi.nlm.nih.gov/38131292/

4. Iida, Aritoshi, Takano, Kyoko, Takeshita, Eri, Inoue, Ken, Goto, Yu-Ichi. 2019. A novel PAK3 pathogenic variant identified in two siblings from a Japanese family with X-linked intellectual disability: case report and review of the literature. In Cold Spring Harbor molecular case studies, 5, . doi:10.1101/mcs.a003988. https://pubmed.ncbi.nlm.nih.gov/31444167/

5. Felix, Martina, Chayengia, Mrinal, Ghosh, Ritabrata, Sharma, Aditi, Prasad, Mohit. 2015. Pak3 regulates apical-basal polarity in migrating border cells during Drosophila oogenesis. In Development (Cambridge, England), 142, 3692-703. doi:10.1242/dev.125682. https://pubmed.ncbi.nlm.nih.gov/26395489/

6. Duarte, Kévin, Heide, Solveig, Poëa-Guyon, Sandrine, Héron, Delphine, Barnier, Jean-Vianney. 2019. PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration. In Neurobiology of disease, 136, 104709. doi:10.1016/j.nbd.2019.104709. https://pubmed.ncbi.nlm.nih.gov/31843706/

7. Bolamperti, Simona, Saito, Hiroaki, Heerdmann, Sarah, Hesse, Eric, Taipaleenmäki, Hanna. 2024. Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling. In eLife, 13, . doi:10.7554/eLife.94265. https://pubmed.ncbi.nlm.nih.gov/38661167/