Dusp6, also known as MKP3, is a dual-specificity phosphatase with a conserved function in the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) [2,5]. It is involved in multiple signaling pathways, and its dysregulation is associated with various biological processes and diseases. Genetic models, such as gene knockout (KO) mouse models, have been crucial for studying its function.

In myeloid malignancies, Dusp6 perturbation inhibited S6, JAK-STAT signaling, and inflammatory cytokine production, while also suppressing ribosomal S6 kinase (RSK)1. Ectopic expression of Dusp6 mediated JAK2-inhibitor resistance, and its inhibition suppressed disease development in MPN mouse models and sAML patient-derived xenografts (PDXs) [1]. In the context of myocardial infarction, Dusp6 deficiency attenuated neutrophil-mediated cardiac damage in the acute inflammatory phase, improving cardiac outcomes [2]. In HER2+ breast cancer, DUSP6 overexpression conferred apoptosis resistance, and its pharmacological blockade prevented therapy tolerance development under HER2 inhibitor therapy [3]. In colorectal cancer, DUSP6 regulated Notch1 signaling, with elevated DUSP6 expression correlating with increased Notch1 intracellular domain levels and enhanced cell proliferation, and Dusp6 deficiency reducing CRC development in mice [4]. In hair follicle stem cells (HFSCs), overexpression of Dusp6 suppressed cell proliferation by inducing G1-phase cell cycle arrest and promoting apoptosis [6].

In summary, Dusp6 plays a significant role in various biological processes and disease conditions. KO mouse models and other loss-of-function experiments have revealed its importance in myeloid malignancies, cardiac repair after myocardial infarction, breast cancer therapy tolerance, colorectal cancer development, and the regulation of HFSC proliferation. Understanding Dusp6 function provides potential therapeutic targets for these diseases.

References:

1. Kong, Tim, Laranjeira, Angelo B A, Yang, Kangning, Huang, Sidong, Oh, Stephen T. 2022. DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression. In Nature cancer, 4, 108-127. doi:10.1038/s43018-022-00486-8. https://pubmed.ncbi.nlm.nih.gov/36581736/

2. Zhou, Xiaohai, Zhang, Chenyang, Wu, Xueying, Zhu, Xiaojun, Xiong, Jing-Wei. 2022. Dusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction. In Nature communications, 13, 6672. doi:10.1038/s41467-022-33631-z. https://pubmed.ncbi.nlm.nih.gov/36335128/

3. Momeny, Majid, Tienhaara, Mari, Sharma, Mukund, Kurppa, Kari J, Westermarck, Jukka. 2024. DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer. In EMBO molecular medicine, 16, 1603-1629. doi:10.1038/s44321-024-00088-0. https://pubmed.ncbi.nlm.nih.gov/38886591/

4. Png, Chin Wen, Weerasooriya, Madhushanee, Li, Heng, Tan, Ker-Kan, Zhang, Yongliang. 2024. DUSP6 regulates Notch1 signalling in colorectal cancer. In Nature communications, 15, 10087. doi:10.1038/s41467-024-54383-y. https://pubmed.ncbi.nlm.nih.gov/39572549/

5. Weng, Yi-Chinn, Huang, Yu-Ting, Chiang, I-Chen, Tan, Tse-Hua, Chou, Wen-Hai. 2023. DUSP6 Deficiency Attenuates Neurodegeneration after Global Cerebral Ischemia. In International journal of molecular sciences, 24, . doi:10.3390/ijms24097690. https://pubmed.ncbi.nlm.nih.gov/37175394/

6. Wang, Qiang, Zhang, Liuming, Qu, Jingwen, Ji, Dejun, Li, Yongjun. 2022. DUSP6 inhibits the proliferation of hair follicle stem cells (HFSCs) in vitro. In Animal biotechnology, 34, 1223-1231. doi:10.1080/10495398.2021.2016433. https://pubmed.ncbi.nlm.nih.gov/37524308/