Novel Roles of the MAP kinase-interacting kinases

Abstract

The MAP kinase-interacting kinases (MNKs) are ubiquitously expressed in mammalian cells. They are activated through MAP kinase pathways and can phosphorylate the eukaryotic translation initiation factor 4E (eIF4E) at a single site. eIF4E plays a key role in protein synthesis and its control. eIF4E and its phosphorylation play important roles in cancer and tumorigenesis. As MNKs play important roles in several diseases, but are not essential to animal development, they may be good targets for cancer therapy. Our recent studies show that the MNKs contribute to the migration of cancer cells. The cytoplasmic FMRP-interacting protein 1 (CYFIP1) is reported as an eIF4E binding partner, and suppresses translation by binding with fragile X mental retardation protein (FMRP) and eIF4E. Our research demonstrates that inhibition of MNKs can also inhibit release of CYFIP1 from eIF4E, which may repress translation of certain mRNAs related to cell migration, including matrix metalloproteinases (MMP3, MMP9) and Vimentin (which serves as a marker of the epithelial-mesenchymal transition). Also, the MNKs were found to be involved in regulating the expression and phosphorylation of N-Myc Downstream Regulated 1 (NDRG1), a protein which is a well-known metastasis suppressor in breast cancers. In addition to functions in cell migration, our previous research shows that MNK2 affects fat mass of mice on a high fat diet. In addition, MNK2KO mice fed a high fat diet are protected from adipose tissue inflammation. Consequently, we focused on MNK functions in inflammation, and this thesis describes the effect by MNK inhibition on the morphology and other features of RAW macrophage cells.