Dusp22, also known as JKAP or JSP-1, is an atypical dual-specificity phosphatase enzyme. It plays essential roles in multiple biological functions such as immune responses and tumor growth, by regulating various kinase signaling pathways through dephosphorylation [1,2,3,4]. It is involved in pathways like EGFR/c-Met, TCR-Lck, and EGFR-AR axes [2,3,4]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In non-alcoholic steatohepatitis (NASH)-hepatocellular carcinoma (HCC), hepatic-specific Dusp22 deletion in mice exacerbates lipid deposition, inflammatory response, fibrosis, and NASH-HCC progression, while its over-expression inhibits these phenotypes. Mechanistically, Dusp22 directly interacts with focal adhesion kinase (FAK) and restrains its phosphorylation, subsequently prohibiting downstream activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) cascades [1]. In lung cancer, genetic deletion of Dusp22 in mice enhances EGFRdel-driven lung tumorigenesis and elevates EGFR activity, and knockdown of Dusp22 using shRNA in cells increases sensitivity to gefitinib [2]. In T-cell activation, genomic deletion of UBR2 attenuates inflammatory phenotypes induced by TCR-triggered Lck activation or Dusp22 knockout, showing the regulatory role of Dusp22 in T-cell-related inflammation [3].

In conclusion, Dusp22 is a crucial regulator in multiple biological processes and diseases. Mouse models, especially KO/CKO models, have revealed its role in diseases like NASH-HCC, lung cancer, and T-cell-related inflammation, by showing how its loss or gain of function affects key signaling pathways. These findings highlight its potential as a therapeutic target in related disease areas.

References:

1. Ge, Chenxu, Tan, Jun, Dai, Xianling, Wang, Bochu, Xu, Minxuan. 2022. Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK. In Nature communications, 13, 5945. doi:10.1038/s41467-022-33493-5. https://pubmed.ncbi.nlm.nih.gov/36209205/

2. Lin, Hsiao-Han, Chang, Cheng-Wei, Liao, Yu-Ting, Tan, Tse-Hua, Lin, Wen-Jye. 2024. DUSP22 inhibits lung tumorigenesis by suppression of EGFR/c-Met signaling. In Cell death discovery, 10, 285. doi:10.1038/s41420-024-02038-8. https://pubmed.ncbi.nlm.nih.gov/38877005/

3. Shih, Ying-Chun, Chen, Hsueh-Fen, Wu, Chia-Ying, Chuang, Huai-Chia, Tan, Tse-Hua. 2024. The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling. In Nature communications, 15, 532. doi:10.1038/s41467-024-44843-w. https://pubmed.ncbi.nlm.nih.gov/38225265/

4. Lin, Hsiu-Ping, Ho, Hui-Min, Chang, Cheng-Wei, Tan, Tse-Hua, Lin, Wen-Jye. 2019. DUSP22 suppresses prostate cancer proliferation by targeting the EGFR-AR axis. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 14653-14667. doi:10.1096/fj.201802558RR. https://pubmed.ncbi.nlm.nih.gov/31693867/