Mixed Lineage Kinase

Mixed Lineage Kinase

Mixed-lineage kinases (MLKs) are serine/threonine protein kinases that regulate signalling by the c-Jun amino-terminal kinase (JNK) and p38 mitogen-activated-protein kinase (MAPK) pathways.

An overview of MLKs

Mixed lineage kinases (MLKs), the Ser/Thr protein kinases, belong to the MAP kinase kinase kinase (MAP3K) family, which are involved in the activation of mitogen activated protein kinases (MAPKs), is the most classic small molecule inhibitor of MLK family, blocking the JNK pathway and leading to the cell death, which is significant in Alzheimer’s disease and other neurodegenerative diseases. URMC-099 is a MLK3 inhibitor with oral activity, which is able to inhibit the release of TNF in microglial cells induced by lipopolysaccharide.

MLKs and diseases

Accumulating evidence shows that MLKs is associated with diet-induced insulin resistance and obesity by activating JNK pathway. In the liver, the MLKs will result in non-alcoholic steatohepatitis. Cytokine production is regulated by JNK and p38 MAPK signaling pathways, indicating the diseases of chronic inflammation. The MLK family members are highly expressed in the brain and contribute to several neurodegenerative diseases. Based on the relationship between MLKs and cell cycle, invasion and migration, it is easily speculated that MLKs are carcinogenic. It is also reported MLKs play a central role in cardiovascular diseases.

References:

1. Chadee, D. N. Involvement of mixed lineage kinase 3 in cancer. Canadian Journal of Physiology & Pharmacology 91, 268 (2013).

2. Craige, S. M., Reif, M. M. & Kant, S. Mixed - Lineage Protein kinases (MLKs) in inflammation, metabolism, and other disease states. Biochimica et biophysica acta 1862, 1581 (2016).

3. Wang, L. H., Besirli, C. G. & Jr, E. M. J. MIXED-LINEAGE KINASES: A Target for the Prevention of Neurodegeneration. Annu Rev Pharmacol Toxicol 44, 451-474 (2004).

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