Phosphorylation and Signal Transduction Pathways in Translational Control

Abstract

Protein synthesis, including the translation of specific messenger RNAs (mRNAs), is regulated by extracellular stimuli such as hormones and by the levels of certain nutrients within cells. This control involves several well-understood signaling pathways and protein kinases, which regulate the phosphorylation of proteins that control the translational machinery. These pathways include the mechanistic target of rapamycin complex 1 (mTORC1), its downstream effectors, and the mitogen-activated protein (MAP) kinase (extracellular ligand-regulated kinase [ERK]) signaling pathway. This review describes the regulatory mechanisms that control translation initiation and elongation factors, in particular the effects of phosphorylation on their interactions or activities. It also discusses current knowledge concerning the impact of these control systems on the translation of specific mRNAs or subsets of mRNAs, both in physiological processes and in diseases such as cancer.

Figure 1.

Major signaling connections to the translational machinery. This simplified schematic shows the main signaling links to the translational machinery. Solid lines depict direct links and dashed lines indirect ones (involving multiple components, for example). (P) indicates phosphorylation events, green indicates activation, red indicates an inhibitory phosphorylation, and gray denotes that the functional consequence is unclear. Not all the components or phosphorylation sites mentioned in the text are shown. Question marks denote some of the open questions described in the text.

Figure 2.

Signaling links to the cap-binding initiation machinery. S6 kinase (S6K) indicates S6 kinases 1 and 2, and MAP kinase-interacting kinase (MNK) denotes MNK1/2. Not all phosphorylation events are depicted. Thin solid gray lines denote direct phosphorylation; the dashed gray line indicates that mechanistic target of rapamycin complex 1 (mTORC1) signaling can promote eukaryotic initiation factor (eIF)4G/eIF3 binding. Step A, stimulation of cells (e.g., with insulin or a growth factor), leads to the activation of kinases including mTORC1, MNKs, and S6Ks, leading to Step B where different protein:protein interactions occur and assembly of eIF4F, together with eIF3 and 40S ribosomal subunits. Please see the text for further information.

Figure 3.

Regulation of eukaryotic elongation factor 2 (eEF2) kinase. The principal domains of eEF2K are depicted schematically, not to scale, including the CaM-binding site and a region at the extreme carboxyl terminus, which is required for eEF2K to phosphorylate eEF2 and may interact directly with that protein. Known phosphorylation sites are shown; orange for inhibitory sites, green for one that activates eEF2K, and gray for ones whose function is not clear or do not affect activity. Solid lines indicate direct phosphorylation; dashed ones denote indirect or unclear connections.