Signaling Pathways Involved in the Regulation of mRNA Translation

Abstract

Translation is a key step in the regulation of gene expression and one of the most energy-consuming processes in the cell. In response to various stimuli, multiple signaling pathways converge on the translational machinery to regulate its function. To date, the roles of phosphoinositide 3-kinase (PI3K)/AKT and the mitogen-activated protein kinase (MAPK) pathways in the regulation of translation are among the best understood. Both pathways engage the mechanistic target of rapamycin (mTOR) to regulate a variety of components of the translational machinery. While these pathways regulate protein synthesis in homeostasis, their dysregulation results in aberrant translation leading to human diseases, including diabetes, neurological disorders, and cancer. Here we review the roles of the PI3K/AKT and MAPK pathways in the regulation of mRNA translation. We also highlight additional signaling mechanisms that have recently emerged as regulators of the translational apparatus.

Keywords: MAPK; MNK; RSK; eIF4E; mRNA; mRNA translation; mTOR; mitogen-activated protein kinases; protein phosphorylation; signal transduction; translational control.

FIG 1

Schematic representation of mTOR signaling to the translational machinery. Growth factors stimulate mTORC1 signaling by activating receptor tyrosine kinases (RTKs) located at the plasma membrane. Various adaptor proteins convert these extracellular signals by stimulating the PI3K/AKT and Ras/ERK pathways. Many additional cues promote mTORC1 activation, including glucose and amino acids via small Rag GTPases, which help translocate mTORC1 to the surface of lysosomes. In turn, insufficient energy resources (energy stress) and hypoxia inactivate mTORC1 via the LKB1/AMPK pathway and REDD1, respectively. mTORC2 also responds to agonists that stimulate the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) and promotes the activity of AGC kinase family members (PKC, AKT, and SGK) by phosphorylating residues located in their hydrophobic motifs. mTORC1 modulates mRNA translation by promoting the phosphorylation of downstream substrates, including the 4E-BPs and S6Ks, the latter having phosphorylation substrates of their own (e.g. eIF4B, rpS6, PDCD4, and SKAR). Red T-bars represent inhibitory signals, whereas black arrows indicate stimulatory signals. P denotes phosphorylation. Abbreviations and detailed explanations about this signaling network are provided in the text.

FIG 2

The mTOR and MAPK pathways affect the translatome by modulating the expression of specific subsets of mRNAs. Phosphorylation of the 4E-BPs by mTOR leads to their dissociation from eIF4E, which stimulates the interaction of eIF4E with eIF4G and assembly of the eIF4F complex. mTOR also promotes S6K-dependent phosphorylation of PDCD4 and eIF4B, which in turn regulate eIF4A levels and activity, respectively. eIF4E is the most limiting subunit of the eIF4F complex and is thus critical for the recruitment of eIF4A to the mRNA and unwinding of the secondary structure of its 5′UTR during ribosome scanning toward the initiation codon. The Ras/ERK pathway also regulates eIF4A activity by promoting RSK-dependent phosphorylation of eIF4B and PDCD4. eIF4E activity is also regulated by MAPK pathways by direct phosphorylation of eIF4E by the MNK protein kinases. Although the eIF4F complex regulates the translatome at a global scale, each subunit also appears to modulate the translation of specific subsets of transcripts. For instance, overexpression of eIF4E appears to selectively affect translation of mRNAs encoding proteins involved in tumor initiation and maintenance (e.g., cyclins, vascular endothelial growth factor [VEGF], and BCL-xL). Phosphorylation of eIF4E also seems to bolster the translation of mRNAs encoding proteins involved in tumor dissemination (e.g., SNAIL and MMP3). Various stresses activate eIF2 kinases (PERK, PKR, GCN2, and HRI) that phosphorylate eIF2 (alpha subunit), which reduces global protein synthesis but promotes the translation of mRNAs containing upstream open reading frames (uORFs), such as those encoding ATF4, CHOP, and GADD34. eIF4A promotes the translation of mRNAs with G/C-rich 5′ UTR sequences, such as the 12-nucleotide guanine quartet (CGG)₄ motif, which can form RNA G-quadruplex structures. Red T-bars represent inhibitory signals, whereas black arrows indicate stimulatory signals. P denotes phosphorylation. Abbreviations and detailed explanations about this signaling network are provided in the text.

FIG 3

Schematic representation of MAPK signaling to the translational machinery. The Ras/ERK and p38MAPK pathways are activated by a wide range of stimuli, including cytokines, growth factors, and diverse environmental stresses. While many stimuli activate both MAPK pathways, stress stimuli and growth factors typically activate the p38MAPK and Ras/ERK signaling, respectively. While Ras/ERK signaling stimulates the activity of both RSK and MNK, the latter is also responsive to agonists of the p38MAPK pathway. MNK interacts with eIF4G and phosphorylates eIF4E on Ser209, a site that increases its oncogenic potential and facilitates the translation of specific mRNAs. Following activation of the Ras/ERK pathway, RSK phosphorylates rpS6, eIF4B, PDCD4, and eEF2K, which are important regulators of translation. RSK also modulates mTORC1 signaling by phosphorylating TSC2 and deptor. ERK and RSK regulate LKB1-dependent and -independent phosphorylation of raptor, resulting in increased mTORC1 signaling. ERK and RSK also collaborate in the regulation of ribosome biogenesis by promoting TIF-1A phosphorylation. Red T-bars represent inhibitory signals, whereas black arrows indicate stimulatory signals. P denotes phosphorylation. Abbreviations and detailed explanations about this signaling network are provided in the text.