New frontiers in translational control of the cancer genome - PubMed (original) (raw)

Figure 1. Oncogenic activation of mRNA translation

a | A central output of oncogenic MYC, RAS–MAPK, PI3K–AKT–mTOR and WNT–β-catenin signalling pathways is the aberrant activation of mRNA translation at the initiation and elongation steps. Translation initiation, the first step in this process, is considered the primary rate-limiting step of protein synthesis and typically proceeds in a ‘cap-dependent’ manner that relies on the ability of the eukaryotic translation initiation factor 4F (eIF4F) complex to bind to the 5′ 7-methylguanosine cap present on mature mRNAs. Oncogenic signalling promotes translation initiation predominantly through alterations in the eIF4F complex, which comprises the major cap-binding protein eIF4E, the scaffolding protein eIF4G and the helicase eIF4A. The eIF4F complex drives translation initiation through the ability of eIF4E to bind to the 5′ cap and interact with eIF4G, which recruits the 43S ribosomal pre-initiation complex (comprising a 40S ribosomal subunit, the eIF2–GTP–Met-tRNAiMet ternary complex, eIF3 and several additional accessory factors). Oncogenic signalling can hyperactivate eIF4E through enhanced transcription,, through phosphorylation of eIF4E at serine 209 by the MAPK-interacting serine/threonine kinases (MNKs),, and through mTOR complex 1 (mTORC1)-dependent phosphorylation and inactivation of the eIF4E inhibitors eIF4E-binding proteins (4EBPs),,–,. Upon recruitment of the 43S complex to the 5′ untranslated region of mRNA, it scans in the 5′ to 3′ direction until reaching a start codon, a process facilitated by eIF4A helicase unwinding of secondary structures and promoted by ribosomal protein S6 kinase (S6K)-dependent stimulation of eIF4A activity through inhibition of programmed cell death protein 4 (PDCD4) and activation of eIF2B,. Start codon recognition by the 43S complex is followed by GTP hydrolysis within the ternary complex and joining of the 60S ribosomal subunit to form a translationally competent ribosome. Translation can also be regulated at the elongation stage by oncogenic signalling, largely through S6K-dependent inhibition of eukaryotic translation elongation factor 2 (eEF2) kinase (eEF2K),,. Phosphorylation of eEF2K by S6K relieves its suppression of eEF2 (REF. 205), promoting the codon by codon translocation of the ribosome along the mRNA. Dashed arrows indicate indirect activation. b | Oncogenic activation of translation initiation and elongation supports tumorigenesis in part by driving selective changes in the translation of specific mRNA transcripts independently of alterations in transcript levels or global increases in protein synthesis. This selective translational control of specific mRNA transcripts underlies the acquisition and execution of distinct cancer cell behaviours central to the transformed phenotype, such as increased cell growth and proliferation, altered metabolism, enhanced angiogenesis, proper reactive oxygen species (ROS) control, immune cell recruitment, and invasion and metastasis,. CCL, C-C motif chemokine ligand; CCND3, cyclin D3; FTH1, ferritin heavy polypeptide 1; GCLC, glutamate–cysteine ligase catalytic subunit; MTA1, metastasis-associated 1; PRPS2, phosphoribosyl pyrophosphate synthetase 2; RAPTOR, regulatory associated protein of mTORC1; VEGFA, vascular endothelial growth factor A; YB1, Y-box binding protein 1.