Vav2, a guanine nucleotide exchange factor for Rho family GTPase, is involved in diverse biological processes. It activates Rho GTPases and participates in multiple signaling pathways, playing a crucial role in cell growth, migration, and cytoskeleton dynamics. Genetic models, such as gene knockout mouse models, have been instrumental in studying its functions [2,3,6,9].

In breast cancer, targeting Vav2 can reverse the trastuzumab-refractory microenvironment created by CD16+ fibroblasts, as the trastuzumab-CD16 interaction activates the SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A pathway in these fibroblasts [1]. In esophageal squamous cell carcinoma, Vav2 is required for the Ku70/Ku80 complex formation and non-homologous end-joining repair of DNA damages caused by ionizing radiation, contributing to radioresistance [2]. In spinal motor axon guidance, Vav2 is essential for Netrin-1-regulated pathfinding of spinal lateral motor column neurons [3]. In the islet β-cell, the Tiam1/Vav2-Rac1 axis has both beneficial and detrimental roles in islet function and dysfunction [4]. Vav2 is also a novel APP-interacting protein regulating APP protein level [5], promotes ductus arteriosus anatomic closure through SMC remodeling [6], and its inhibition by columbianadin can ameliorate rheumatoid arthritis [7]. In both keratinocytes and oral squamous cell carcinoma, Vav2 orchestrates the interplay between regenerative proliferation and ribogenesis [8]. In skeletal muscle, Vav2's catalytic activity modulates the signaling output of the IGF1-and insulin-stimulated phosphatidylinositol 3-kinase pathway, affecting muscle growth and metabolic homeostasis [9]. In prostate cancer, VAV2 drives EGFR-mediated Rac1 responses, and its overexpression is associated with poor prognosis [10].

In summary, Vav2 is essential in various biological processes from embryonic development to tissue homeostasis and disease. Model-based research, especially gene knockout mouse models, has revealed its critical roles in cancer, radiation resistance, neurological development, metabolic regulation, and other disease areas, providing potential therapeutic targets for these conditions.

References:

1. Liu, Xinwei, Lu, Yiwen, Huang, Jingying, Gu, Yuanting, Su, Shicheng. . CD16+ fibroblasts foster a trastuzumab-refractory microenvironment that is reversed by VAV2 inhibition. In Cancer cell, 40, 1341-1357.e13. doi:10.1016/j.ccell.2022.10.015. https://pubmed.ncbi.nlm.nih.gov/36379207/

2. Liu, Weiling, Miao, Chuanwang, Zhang, Shaosen, Lin, Dongxin, Wu, Chen. 2021. VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance. In Signal transduction and targeted therapy, 6, 322. doi:10.1038/s41392-021-00735-9. https://pubmed.ncbi.nlm.nih.gov/34462423/

3. Tsou, Yi-Syue, Wang, Chih-Yang, Chang, Ming-Yuan, Chuang, Jian-Ying, Kao, Tzu-Jen. 2021. Vav2 is required for Netrin-1 receptor-class-specific spinal motor axon guidance. In Developmental dynamics : an official publication of the American Association of Anatomists, 251, 444-458. doi:10.1002/dvdy.409. https://pubmed.ncbi.nlm.nih.gov/34374463/

4. Kowluru, Anjaneyulu. 2017. Tiam1/Vav2-Rac1 axis: A tug-of-war between islet function and dysfunction. In Biochemical pharmacology, 132, 9-17. doi:10.1016/j.bcp.2017.02.007. https://pubmed.ncbi.nlm.nih.gov/28202288/

5. Zhang, Youjia, Yang, Xiaxin, Liu, Yongrui, Wu, Bo, Wang, Junfeng. 2022. Vav2 is a novel APP-interacting protein that regulates APP protein level. In Scientific reports, 12, 12752. doi:10.1038/s41598-022-16883-z. https://pubmed.ncbi.nlm.nih.gov/35882892/

6. Chen, Yinghui, Wu, Yizhuo, Feng, Weiqi, Lu, Yanan, Yu, Yu. 2023. Vav2 promotes ductus arteriosus anatomic closure via the remodeling of smooth muscle cells by Rac1 activation. In Journal of molecular medicine (Berlin, Germany), 101, 1567-1585. doi:10.1007/s00109-023-02377-6. https://pubmed.ncbi.nlm.nih.gov/37804474/

7. Han, Yuli, Liu, Changqing, Chen, Shujing, Du, Kunze, Chang, Yanxu. 2024. Columbianadin ameliorates rheumatoid arthritis by attenuating synoviocyte hyperplasia through targeted vimentin to inhibit the VAV2/Rac-1 signaling pathway. In Journal of advanced research, , . doi:10.1016/j.jare.2024.09.030. https://pubmed.ncbi.nlm.nih.gov/39369957/

8. Fernández-Parejo, Natalia, Lorenzo-Martín, L Francisco, García-Pedrero, Juana M, Dosil, Mercedes, Bustelo, Xosé R. 2024. VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma. In Scientific reports, 14, 4060. doi:10.1038/s41598-024-54808-0. https://pubmed.ncbi.nlm.nih.gov/38374399/

9. Rodríguez-Fdez, Sonia, Lorenzo-Martín, L Francisco, Fernández-Pisonero, Isabel, Nogueiras, Rubén, Bustelo, Xosé R. 2020. Vav2 catalysis-dependent pathways contribute to skeletal muscle growth and metabolic homeostasis. In Nature communications, 11, 5808. doi:10.1038/s41467-020-19489-z. https://pubmed.ncbi.nlm.nih.gov/33199701/

10. Baker, Martin J, Zhang, Suli, Zhang, Daniel, Kazanietz, Marcelo G, Cooke, Mariana. 2025. VAV2 drives EGFR-mediated Rac1 responses in prostate cancer. In Molecular cancer research : MCR, , . doi:10.1158/1541-7786.MCR-24-0957. https://pubmed.ncbi.nlm.nih.gov/40183768/