Frk, short for Fyn-related kinase, is a non-receptor tyrosine kinase, a member of the Src-related tyrosine kinase family and BRK family kinases (BFKs) [5]. It is involved in multiple biological processes and signaling pathways, playing a crucial role in cancer biology, antiviral immunity, and cell survival, differentiation, and proliferation. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying its functions.

In cancer, Frk shows a tissue-specific functional paradox. In glioma, overexpression of Frk inhibits growth by reducing integrin subunit β1 (ITGB1) expression and suppressing ITGB1/FAK signaling, and it also promotes the ubiquitination and degradation of YAP via phosphorylation, leading to tumor suppression [1,2]. In breast cancer, overexpression of Frk inhibits cell migration and invasion by suppressing epithelial-mesenchymal transition [8]. However, in non-small cell lung cancer (NSCLC), Frk exerts oncogenic effects. Knockout of Frk in NSCLC cells inhibits proliferation, invasion, and the stemness phenotype, and induces metabolism reprogramming [4,6]. In leukemia, the fusion gene ETV6::FRK in leukaemic cells is sensitive to dasatinib, which represses the FRK-STAT3/STAT5 pathway [3].

In antiviral immunity, Frk positively regulates innate antiviral immunity. In macrophages, Frk phosphorylates TBK1 at tyrosine residues 174 and 179, promoting its K63 ubiquitination and subsequent activation of IRF3, thus enhancing IFN-β production [7]. In HIV-1 infection, the host tyrosine kinase FRK is activated, phosphorylating Vif to enhance its interaction with SHP-1, which inhibits type I IFN production [10]. Also, FRK/RAK is upstream of SHB in some cells, and the FRK/RAK-SHB signaling cascade regulates cell survival, differentiation, and proliferation [9].

In conclusion, Frk has diverse functions in cancer and antiviral immunity. Model-based research, especially KO mouse models, has revealed its complex roles in different biological processes and disease conditions. In cancer, it can act as either a tumor suppressor or an oncogene depending on the tissue type, and in antiviral immunity, it plays a positive regulatory role. Understanding Frk's functions provides potential therapeutic targets for treating cancer and viral infections.

References:

1. Wang, Jun, Cai, Chang, Nie, Dekang, Shi, Qiong, Yu, Rutong. 2019. FRK suppresses human glioma growth by inhibiting ITGB1/FAK signaling. In Biochemical and biophysical research communications, 517, 588-595. doi:10.1016/j.bbrc.2019.07.059. https://pubmed.ncbi.nlm.nih.gov/31395336/

2. Wang, Yan, Wang, Kai, Fu, Jiale, Yu, Rutong, Zhou, Xiuping. . FRK inhibits glioblastoma progression via phosphorylating YAP and inducing its ubiquitylation and degradation by Siah1. In Neuro-oncology, 24, 2107-2120. doi:10.1093/neuonc/noac156. https://pubmed.ncbi.nlm.nih.gov/35723276/

3. Mayumi, Azusa, Imamura, Toshihiko, Yoshida, Hideki, Yasuda, Takahiko, Iehara, Tomoko. 2023. Leukaemic cells expressing ETV6::FRK are sensitive to dasatinib in vivo. In EJHaem, 4, 751-755. doi:10.1002/jha2.701. https://pubmed.ncbi.nlm.nih.gov/37601849/

4. Huang, Hong, Wang, Yan, Gan, Jiadi, Yang, Yongfeng, Liu, Dan. . FRK exerts oncogenic effects by targeting NQO2 via exosomal miR-9-3p to regulate mitochondrial function. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38, e70221. doi:10.1096/fj.202400951R. https://pubmed.ncbi.nlm.nih.gov/39625368/

5. Goel, Raghuveera Kumar, Lukong, Kiven Erique. . Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology. In Cancer metastasis reviews, 35, 179-99. doi:10.1007/s10555-016-9623-3. https://pubmed.ncbi.nlm.nih.gov/27067725/

6. Zhang, Li, Yang, Yongfeng, Chai, Li, Chen, Fei, Li, Weimin. 2019. FRK plays an oncogenic role in non-small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming. In International journal of cancer, 146, 208-222. doi:10.1002/ijc.32530. https://pubmed.ncbi.nlm.nih.gov/31251822/

7. Zhang, Xiaomei, You, Ying, Xiong, Tingrong, Wen, Xiaohua, Zhao, Congcong. 2025. Frk positively regulates innate antiviral immunity by phosphorylating TBK1. In Frontiers in microbiology, 16, 1525648. doi:10.3389/fmicb.2025.1525648. https://pubmed.ncbi.nlm.nih.gov/40012791/

8. Ogunbolude, Yetunde, Dai, Chenlu, Bagu, Edward T, Bonham, Keith, Lukong, Kiven Erique. 2017. FRK inhibits breast cancer cell migration and invasion by suppressing epithelial-mesenchymal transition. In Oncotarget, 8, 113034-113065. doi:10.18632/oncotarget.22958. https://pubmed.ncbi.nlm.nih.gov/29348886/

9. Annerén, Cecilia, Lindholm, Cecilia K, Kriz, Vitezslav, Welsh, Michael. . The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation. In Current molecular medicine, 3, 313-24. doi:. https://pubmed.ncbi.nlm.nih.gov/12776987/

10. Wang, Yu, Qian, Gui, Zhu, Lingyan, Zou, Quanming, Yan, Dapeng. 2021. HIV-1 Vif suppresses antiviral immunity by targeting STING. In Cellular & molecular immunology, 19, 108-121. doi:10.1038/s41423-021-00802-9. https://pubmed.ncbi.nlm.nih.gov/34811497/