Signalling to eIF4E in cancer

Abstract

Translational control plays a critical role in the regulation of gene expression in eukaryotes and affects many essential cellular processes, including proliferation, apoptosis and differentiation. Under most circumstances, translational control occurs at the initiation step at which the ribosome is recruited to the mRNA. The eukaryotic translation initiation factor 4E (eIF4E), as part of the eIF4F complex, interacts first with the mRNA and facilitates the recruitment of the 40S ribosomal subunit. The activity of eIF4E is regulated at many levels, most profoundly by two major signalling pathways: PI3K (phosphoinositide 3-kinase)/Akt (also known and Protein Kinase B, PKB)/mTOR (mechanistic/mammalian target of rapamycin) and Ras (rat sarcoma)/MAPK (mitogen-activated protein kinase)/Mnk (MAPK-interacting kinases). mTOR directly phosphorylates the 4E-BPs (eIF4E-binding proteins), which are inhibitors of eIF4E, to relieve translational suppression, whereas Mnk phosphorylates eIF4E to stimulate translation. Hyperactivation of these pathways occurs in the majority of cancers, which results in increased eIF4E activity. Thus, translational control via eIF4E acts as a convergence point for hyperactive signalling pathways to promote tumorigenesis. Consequently, recent works have aimed to target these pathways and ultimately the translational machinery for cancer therapy.

Keywords: cancer therapy; eukaryotic translation initiation factor 4E (eIF4E); eukaryotic translation initiation factor 4E-binding proteins (4E-BPs); mechanistic/mammalian target of rapamycin (mTOR); mitogen-activated protein kinase-interacting kinase 1/2 (Mnk1/2); phospho-4E.

Figure 1. Model of cap dependent translation initiation

eIF4F binds to the m⁷G cap structure via the cap-binding protein eIF4E. eIF4G is a scaffold protein which also binds to the RNA helicase eIF4A and eIF3, which in turn recruits the 43S pre-initiation complex (PIC). The PIC consists of the 40S ribosomal subunit, eIF2-GTP-Met-tRNAi and several other initiation factors, which are indicated. eIF4A melts the secondary structure in the 5′-UTR and the PIC scans the mRNA until it encounters the AUG start codon where the 60S subunit joins, followed by peptide chain synthesis. eIF4G also binds to PABP which brings about the circularization of the mRNA allowing for efficient ribosome recycling.

Figure 2. Signal transduction pathways converging on eIF4E

The PI3K pathway is activated in response to many extracellular stimuli resulting in the activation of the downstream serine/threonine kinase, mTOR. mTOR is a multi-domain protein which associates with several binding partners to form two different complexes mTORC1 and mTORC2. mTORC1 phosphorylates the translation repressors 4E-BPs, which then dissociate from eIF4E, allowing eIF4F formation and thus promoting translation. Mitogenic and stress signals activate components of the MAPK pathway including the ERK and p38 MAP kinase. Both converge to activate Mnk1/2, which bind to eIF4G and phosphorylate eIF4E at Ser²⁰⁹. Both pathways are hyperactivated in the majority of human malignancies. Drugs targeting, these signalling pathways and translation initiation factors are shown in red.

Figure 3. Targeting eIF4E in tumour heterogeneity

A schematic diagram illustrating a simplified version of diversity within a hypothetical heterogeneous tumour. Sub-populations of cells expressing HER2 (green), ERα (blue) or presenting BRCA1/2 mutations (red) are shown. In contrast, all tumour cells contain elevated eIF4E. The tumours containing the indicated targets are treated in the clinic by the corresponding drugs listed in the figure. We hypothesize that direct eIF4E inhibitors will target all types of tumour cells, regardless of their genetic make-up.