Tuning Specific Translation in Cancer Metastasis and Synaptic Memory: Control at the MNK–eIF4E Axis

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 41; no. 10; pp. 847 - 858
• Main Authors: Bramham, Clive R., Jensen, Kirk B., Proud, Christopher G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-10-2016
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Autism spectrum disorders; cytoplasmic fragile-X mental retardation protein; epithelial-mesenchymal transition; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - metabolism; Gene Expression Regulation, Neoplastic; Humans; long-term synaptic plasticity; MAP kinase-interacting kinase; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neuronal Plasticity; Phosphorylation; Protein Binding; Protein Biosynthesis; protein synthesis; RNA Caps - genetics; RNA Caps - metabolism; Signal Transduction; Synapses - genetics; Synapses - metabolism; long-term synaptic plasticity; Autism spectrum disorders; protein synthesis; MAP kinase-interacting kinase; epithelial-mesenchymal transition; cytoplasmic fragile-X mental retardation protein
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2016.07.008

The eukaryotic translation initiation factor (eIF) 4E, which binds to the 5’-cap of mRNA, undergoes phosphorylation on a single conserved serine, executed by the mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs). However, the functional consequences and physiological roles of MNK signalling have remained obscure. Now, new pharmacological and genetic tools have provided unprecedented insights into the function of MNKs and eIF4E phosphorylation. The studies suggest that MNKs control the translation of specific mRNAs in cancer metastasis and neuronal synaptic plasticity by a novel mechanism involving the regulation of the translational repressor, cytoplasmic fragile-X protein-interacting protein 1 (CYFIP1). These recent breakthroughs go a long way to resolving the longstanding enigma and controversy surrounding the function of the MNK–eIF4E axis in cancer cell biology and neurobiology.
While it has been known for 20 years that eIF4E is phosphorylated by MNKs, the role of eIF4E phosphorylation and these protein kinases remain unclear.
MNK signalling regulates the translation of specific mRNAs for proteins involved in cancer metastasis and long-term synaptic plasticity.
MNKs regulate the binding of eIF4E to partner proteins, such as the initiation factor scaffold protein eIF4G and the fragile X mental retardation protein/cytoplasmic FRMP-binding protein (FMRP/CYFIP1) translation repressor complex.
MNK thereby regulates FMRP targets and other mRNAs involved in cytoskeletal regulation and growth.