MAP4K3, also named GLK, is a serine/threonine kinase belonging to the mammalian Ste20-like kinase family. It serves as an upstream activator of the MAPK JNK under environmental stress and proinflammatory cytokines, and is involved in multiple key biological pathways such as mTOR signaling, autophagy regulation, and T-cell activation [1].

In T-cell-specific GLK transgenic mice and GLK-deficient mice, GLK was found to directly interact with and activate PKCθ, leading to activation of IKK/NF-κB, and thus playing a crucial role in T-cell-mediated immune responses. GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Also, GLK overexpression in T cells promotes IL-17A transcription. In cancer, GLK overexpression in tissues is correlated with cancer recurrence in human lung and liver cancer, and GLK promotes cancer metastasis by phosphorylating and activating IQGAP1 [1,3]. Moreover, MAP4K3 was shown to inhibit Sirtuin-1 to repress the LKB1-AMPK pathway, promoting amino-acid-dependent activation of the mTORC1 complex, and to regulate autophagy via phosphorylation of TFEB [2,4].

In conclusion, MAP4K3 plays essential roles in multiple biological processes including cell proliferation, autophagy, T-cell activation, and metabolism. Studies using GLK-deficient and T-cell-specific GLK transgenic mice have revealed its significant contributions to autoimmune diseases and cancer. Targeting MAP4K3 may potentially be useful for treating/preventing these diseases [1].

References:

1. Chuang, Huai-Chia, Tan, Tse-Hua. 2019. MAP4K3/GLK in autoimmune disease, cancer and aging. In Journal of biomedical science, 26, 82. doi:10.1186/s12929-019-0570-5. https://pubmed.ncbi.nlm.nih.gov/31640697/

2. Branch, Mary Rose, Hsu, Cynthia L, Ohnishi, Kohta, Hunter, Tony, La Spada, Albert R. 2023. MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex. In Life science alliance, 6, . doi:10.26508/lsa.202201525. https://pubmed.ncbi.nlm.nih.gov/37221017/

3. Chuang, Huai-Chia, Chang, Chih-Chi, Teng, Chiao-Fang, Lyu, Ping-Chiang, Tan, Tse-Hua. 2019. MAP4K3/GLK Promotes Lung Cancer Metastasis by Phosphorylating and Activating IQGAP1. In Cancer research, 79, 4978-4993. doi:10.1158/0008-5472.CAN-19-1402. https://pubmed.ncbi.nlm.nih.gov/31431460/

4. Hsu, Cynthia L, Lee, Elian X, Gordon, Kara L, Hunter, Tony, La Spada, Albert R. 2018. MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB. In Nature communications, 9, 942. doi:10.1038/s41467-018-03340-7. https://pubmed.ncbi.nlm.nih.gov/29507340/