Map4k1, also known as Hematopoietic Progenitor Kinase1 (HPK1), is a serine/threonine kinase. It is a member of Ste20-like kinases and functions as an intracellular negative regulator, mainly in hematopoietic lineage cells. It is involved in multiple signaling pathways such as TCR, BCR, and is linked to cytokine-cytokine receptor interactions and chemokine signaling pathways. It plays a crucial role in immune regulation and has implications for various biological processes and diseases [2,3,4,7].

In glioblastoma, MAP4K1 silencing inhibited GBM cell proliferation and glioma growth, suggesting its oncogenic role via the intrinsic IL-18/IL-18R pathway and its contribution to immune evasion by reducing CD8+ T-cell infiltration [1]. In AML, MAP4K1 was highly expressed in drug-resistant cell lines, and its overexpression induced drug resistance and predicted poor prognosis. In vitro, it modulated the cell cycle through MAPK and DNA damage/repair pathways, indicating its potential as a target for AML therapies [5]. In MAP4K1KO mice, tumors grew slower, and infiltrating T cells were less exhausted and more active, highlighting its role in T-cell dysfunction and its potential as a druggable target for immunotherapies [2]. In NK cells, conditional HPK1 overexpression exacerbated melanoma lung metastasis, while MAP4K1-deficient mice were resistant to metastasis, suggesting HPK1 as an intracellular checkpoint controlling NK-target cell responses during metastatic progression [6].

In conclusion, Map4k1 plays significant roles in various disease conditions, especially in cancer. Its functions span from promoting tumor growth and drug resistance to modulating immune cell functions. Studies using Map4k1 KO mouse models have been instrumental in uncovering its roles in glioblastoma, AML, and metastatic melanoma, providing valuable insights for developing targeted therapies in these disease areas.

References:

1. Sun, Jin-Min, Fan, Hong-Ye, Zhu, Yan, Zhang, Dao-Yong, Hou, Xiao-Yu. 2023. Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration. In Life science alliance, 6, . doi:10.26508/lsa.202301966. https://pubmed.ncbi.nlm.nih.gov/37734869/

2. Si, Jingwen, Shi, Xiangjun, Sun, Shuhao, Wei, Lai, Liao, Xuebin. 2020. Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies. In Cancer cell, 38, 551-566.e11. doi:10.1016/j.ccell.2020.08.001. https://pubmed.ncbi.nlm.nih.gov/32860752/

3. He, Tian-Sheng, Huang, Jingping, Chen, Tian, Yu, Jingge, Xu, Liang-Guo. 2021. The Kinase MAP4K1 Inhibits Cytosolic RNA-Induced Antiviral Signaling by Promoting Proteasomal Degradation of TBK1/IKKε. In Microbiology spectrum, 9, e0145821. doi:10.1128/Spectrum.01458-21. https://pubmed.ncbi.nlm.nih.gov/34908452/

4. Schlicher, Lisa, Green, Luke G, Romagnani, Andrea, Renner, Florian. 2023. Small molecule inhibitors for cancer immunotherapy and associated biomarkers - the current status. In Frontiers in immunology, 14, 1297175. doi:10.3389/fimmu.2023.1297175. https://pubmed.ncbi.nlm.nih.gov/38022587/

5. Ling, Qing, Li, Fenglin, Zhang, Xiang, Wang, Yungui, Jin, Jie. 2021. MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway. In EBioMedicine, 69, 103441. doi:10.1016/j.ebiom.2021.103441. https://pubmed.ncbi.nlm.nih.gov/34166980/

6. Choi, Woo Seon, Kwon, Hyung-Joon, Yi, Eunbi, Sung, Chang Ohk, Kim, Hun Sik. 2024. HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2400920. doi:10.1002/advs.202400920. https://pubmed.ncbi.nlm.nih.gov/38828677/

7. Chen, Hui, Guan, Xiangna, He, Chi, Lin, Xingyu, Liao, Xuebin. 2024. Current strategies for targeting HPK1 in cancer and the barriers to preclinical progress. In Expert opinion on therapeutic targets, 28, 237-250. doi:10.1080/14728222.2024.2344697. https://pubmed.ncbi.nlm.nih.gov/38650383/