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Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
When inactive, the initiation factors eIF3 and eIF4 are bound to the signalling proteins S6K1 and 4E-BP1, respectively. Resistance exercise, in particular, nutrients such as essential amino acids, and hormones such as insulin, all activate mTORC1, which, in turn, phosphorylates S6K1 and 4E-BP1 (and various other proteins in the mTOR signalling pathway). As a consequence, eIF3 and eIF4 detach from S6K1 and 4E-BP1 and contribute to the assembly of ribosomes.
Protein Phosphorylation
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Factors involved in RNA translation may be substrates of the Src kinase. The eukaryotic initiation factor 4F (IF-4F) is a three-subunit complex that binds the 5′ cap structure of eukaryotic mRNA. The IF-4F facilitates ribosome binding by unwinding the secondary structure in the mRNA 5′ noncoding region. The limiting component of the IF-4F complex is a 24-kDa cap-binding phosphoprotein, IF-4E, and the Src kinase is involved in the phosphorylation of this protein.364 Src variants with transforming potential, including the v-Src oncoprotein, could release cells from the requirement for extracellular signals to modulate 1F-4E phosphorylation, allowing the cells to proliferate in the absence of serum or growth factors. Phosphorylation of RNA translation factors may be a common pathway for the signaling mechanisms of oncoproteins and growth factors.
An overview of rational design of mRNA-based therapeutics and vaccines
Published in Expert Opinion on Drug Discovery, 2021
Kenneth K.W. To, William C.S. Cho
Poly(A) tails are non-templated addition of adenosine residues at the 3ʹ ends of eukaryotic mRNAs. All cellular protein encoding mRNAs with a few exceptions (e.g. histone) have a poly(A) tail. An optimal length of poly(A) tail is crucial for efficient translation and enhancing mRNA stability [73]. In mammalian cells, most actively translated mRNAs contain a poly(A) tail with around 100–250 adenosine residues [74]. For exogenous administration of mRNA therapeutics, it has been demonstrated that at least 20 adenosines within the poly(A) tail are needed for effective translation [75]. The poly(A) tail binds to various polyadenosyl-binding proteins (PABP), which subsequently recruit the eukaryotic initiation factor 4 G (eIF4G) and increase affinity to the mRNA cap to form circular mRNA [73]. Generally, translation efficiency is proportional to the number of adenosines within a single poly(A) tail [76,77].
Approaching complexity: systems biology and ms-based techniques to address immune signaling
Published in Expert Review of Proteomics, 2020
Joseph Gillen, Caleb Bridgwater, Aleksandra Nita-Lazar
In the study by Howden et al., the proteomes of naïve CD4+ and CD8+ T cells were examined before and after antigen activation. Nearly all (93% and 91%) proteins were affected by the activation with the majority (54% and 56%) of proteins increasing in abundance. By examining the specific proteins with changing abundances, the authors explained the previously reported differences in nutrient uptake by CD4+ effector cells versus CD8+ effector cells: CD8+ have an increased abundance of glucose and amino acid transporters in response to stimuli. In addition, mRNA translation regulators were accumulated following activation, including eukaryotic initiation factor 4F (eIF4F) complexes and eukaryotic initiation factor 2 (eIF2) complexes. Increase in these complexes was related to the increased protein synthesis of activated T cells. Interestingly, the study identified also several environmental-sensing molecules with increased abundances following activation. Combining these data with previous reports on protein function allowed to identify the nutrient-sensing kinase mTORC1 as a key regulator of T cell differentiation by affecting glucose transport, glycolysis, fatty acid metabolism, translation, and cell adhesion [29].
Noradrenergic gating of long-lasting synaptic potentiation in the hippocampus: from neurobiology to translational biomedicine
Published in Journal of Neurogenetics, 2018
Peter V. Nguyen, Jennifer N. Gelinas
One important process where various signals and transmitters can act to regulate protein synthesis is at the level of translation initiation, a rate-limiting step in translation of many species of mRNA. Here, different protein kinases act to phosphorylate eukaryotic initiation factors (eIFs) involved in the assembly of translation initiation complexes that promote mRNA binding to ribosomal proteins (Costa-Mattioli et al., 2009). For example, two key protein kinases, extracellular signal-regulated protein kinase (ERK) and mammalian target of rapamycin (mTOR), play an important role in formation of the eukaryotic initiation factor 4F (eIF4F) complex (Gelinas et al., 2007; Kelleher, Govindarajan, & Tonegawa, 2004; Klann, Antion, Banko, & Hou, 2004; Tsokas, Ma, Iyengar, Landau, & Blitzer, 2007). The eIF4F initiation complex is assembled from the initiation factors eIF4A, 4E, and 4 G (Figure 1). In the basal state, formation of eIF4F is restrained by binding of eIF4E to the inhibitory protein, 4E-binding protein (4E-BP) (Banko et al., 2005). Phosphorylation of 4E-BP by mTOR triggers the release of eIF4E, which can then associate with eIF4G and form the eIF4F complex (Figure 1). In addition, ERK phosphorylates and activates the protein kinase, Mnk1 (MAPK signal-integrating kinase-1), which in turn phosphorylates 4E to further enhance translation.