Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) regulate the initiation of translation through phosphorylation of eukaryotic initiation factor 4E (eIF4E). Mnk-mediated eIF4E activation promotes cancer development and progression. While the phosphorylation of eIF4E is necessary for oncogenic transformation, the kinase activity of Mnks seems dispensable for normal development.
An overview of MNK
MNK is short for mitogen-activated protein kinase-interacting kinase or mitogen-activated kinase signal-integrating kinase, belonging to the serine/threonine kinase family. In 1997, MNK was first identified as the extracellular regulated kinase (ERK) substrate or binding factor, which played an important role in controlling signals involved mRNA translation through phosphorylation of eukaryotic initiation factor 4E (eIF4E). Eukaryotic initiation factor 4F (elF4F) is a significant translation component, composed of eIF4E, eIF4G, eIF4A. Accumulating evidence shows that MNK and the phosphorylation of eIF4E are involved in cell cycle, progression, survival and motility by regulating the expression of related proteins. Meanwhile, MNK and the phosphorylation of eIF4E are reported to exert multiple biological functions in tumorigenesis or tumor progression.
Major types of MNK
There are two members in the MNK kinase family: MNK1 and MNK2, which were identified as substrates for ERK1 and ERK2, respectively. The structures of MNK1 and MNK2 are similar due to the substantial similarity in coding sequences.
Inhibition of MNK
So far, although there have been more and more studies on the structure and function of MNK, few MNK inhibitors have been reported. At present, three MNK inhibitors were discovered: CGP052088, GCP57380 and Cercosporamide. CGP052088, a derivative of staurosporine, is a broad-spectrum kinase inhibitor, preventing phosphorylation of eIF4E. The potent MNK inhibitor CGP57380 is able to target both MNK1 and MNK2 by reducing eIF4G in the eIF4F complex. Addition to MNK1 and MNK2, CGP052088 also has other targets including CK1, SGK, BRSK2 and DYRK. Cercosporamide was discovered in Cercosporidium henningsii as a host-selective phytotoxin, which could be used as a potent MNK inhibitor.
MNK and diseases
MNK regulates the translation of related proteins through phosphorylation of eIF4E, which plays an important role in tumor cell survival, anti-apoptosis, and metastasis, drug resistance mechanisms. Studies have shown that the overexpression of MNK can be detected in a variety of tumor cells, including prostate cancer, breast cancer, pancreatic cancer, lung cancer, glioma, leukemia, etc.
1. Joshi, S., & Platanias, L. C. (2014). Mnk kinase pathway: cellular functions and biological outcomes. World journal of biological chemistry, 5(3), 321.
2. Proud, C. G. (2015). Mnks, eIF4E phosphorylation and cancer. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 1849(7), 766-773.
3. Diab, S., Kumarasiri, M., Yu, M., Teo, T., Proud, C., Milne, R., & Wang, S. (2014). MAP kinase-interacting kinases—emerging targets against cancer. Chemistry & biology, 21(4), 441-452.
4. Hou, J., Lam, F., Proud, C., & Wang, S. (2012). Targeting Mnks for cancer therapy. Oncotarget, 3(2), 118.