Dock2, also known as dedicator of cytokinesis 2, is an atypical guanine exchange factor specifically expressed in hematopoietic cells. It activates Ras-related C3 botulinum toxin substrate (Rac), regulating cytoskeletal reorganization, and is essential for processes like immune cell migration, activation, proliferation, and function [1,2].

Dock2-knockout mouse models have been used to study its role in various diseases. In abdominal aortic aneurysm (AAA) formation, DOCK2 -/- mice showed attenuation of Ang II-induced AAA formation, with reduced MCP-1 and MMP expression and elastin fragmentation, indicating DOCK2 promotes AAA development by inciting vascular inflammation and elastin degradation [3]. In pleural fibrosis models, DOCK2-knockout mice were protected from Streptococcus pneumoniae-induced fibrosis, impaired lung compliance, and collagen deposition, suggesting DOCK2 contributes to pleural fibrosis by mediating mesothelial to mesenchymal transition [4]. In asthma models, DOCK2 deficiency suppressed airway epithelial-mesenchymal transition, attenuated subepithelial fibrosis, and improved pulmonary function in HDM-induced asthmatic lungs [6]. Also, DOCK2-deficient mice had severely attenuated induction of drug-induced systemic and cutaneous anaphylaxis, with impaired MRGPRB2-mediated Rac activation and PAK1 phosphorylation in mast cells [5]. A patient with a DOCK2 mutation showed decreased NK cell function, degranulation, and cytotoxicity, suggesting DOCK2's importance in the pathogenesis of secondary hemophagocytic lymphohistiocytosis (sHLH) [7].

In conclusion, Dock2 is crucial for immune cell-related functions. Studies using gene-knockout mouse models have revealed its role in diseases such as AAA, pleural fibrosis, asthma, drug-induced anaphylaxis, and sHLH. Understanding Dock2's functions provides insights into the mechanisms of these diseases and potential therapeutic targets.

References:

1. Chen, Yayun, Meng, Fan, Wang, Bingyu, Liu, Yangbin, Liu, Zhiping. 2018. Dock2 in the development of inflammation and cancer. In European journal of immunology, 48, 915-922. doi:10.1002/eji.201747157. https://pubmed.ncbi.nlm.nih.gov/29509960/

2. Ji, Lulin, Xu, Shuquan, Luo, Haiqing, Zeng, Fanwei. 2022. Insights from DOCK2 in cell function and pathophysiology. In Frontiers in molecular biosciences, 9, 997659. doi:10.3389/fmolb.2022.997659. https://pubmed.ncbi.nlm.nih.gov/36250020/

3. Guo, Xia, Cai, Dunpeng, Dong, Kun, Xu, Zaiyan, Chen, Shi-You. 2023. DOCK2 Deficiency Attenuates Abdominal Aortic Aneurysm Formation-Brief Report. In Arteriosclerosis, thrombosis, and vascular biology, 43, e210-e217. doi:10.1161/ATVBAHA.122.318400. https://pubmed.ncbi.nlm.nih.gov/37021575/

4. Qian, Guoqing, Adeyanju, Oluwaseun, Roy, Saptarshi, Idell, Steven, Tucker, Torry A. . DOCK2 Promotes Pleural Fibrosis by Modulating Mesothelial to Mesenchymal Transition. In American journal of respiratory cell and molecular biology, 66, 171-182. doi:10.1165/rcmb.2021-0175OC. https://pubmed.ncbi.nlm.nih.gov/34710342/

5. Kunimura, Kazufumi, Akiyoshi, Sayaka, Uruno, Takehito, Hirotani, Kenichiro, Fukui, Yoshinori. 2023. DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis. In The Journal of allergy and clinical immunology, 151, 1585-1594.e9. doi:10.1016/j.jaci.2023.01.029. https://pubmed.ncbi.nlm.nih.gov/36804596/

6. Shi, Ning, Zhang, Jing, Chen, Shi-You. . DOCK2 Promotes Asthma Development by Eliciting Airway Epithelial-Mesenchymal Transition. In American journal of respiratory cell and molecular biology, 69, 310-320. doi:10.1165/rcmb.2022-0273OC. https://pubmed.ncbi.nlm.nih.gov/36883952/

7. Reiff, Daniel D, Zhang, Mingce, Cron, Randy Q. 2023. DOCK2 Mutation and Recurrent Hemophagocytic Lymphohistiocytosis. In Life (Basel, Switzerland), 13, . doi:10.3390/life13020434. https://pubmed.ncbi.nlm.nih.gov/36836791/