sharing sensitive information, make sure youre on a federal Salubrinal and guanabenz are inhibitors of phosphatase and inhibit eIF2 dephosphorylation. Would you like email updates of new search results? Elatol, a marine natural compound, is a novel eIF4A-specific inhibitor which functions through binding the target at key sites in the helicase core of eIF4A and shows broad activity against multiple tumor types (Fig. Please enable it to take advantage of the complete set of features! Schematic representation of PI3K and MAPK signaling to mTORC1. This site needs JavaScript to work properly. [5], eIF2 is the main protein complex responsible for delivering the initiator tRNA to the P-site of the preinitiation complex, as a ternary complex containing Met-tRNAiMet and GTP (the eIF2-TC). 8600 Rockville Pike Two of the subunits, PRAS40 and Deptor [15], are negative regulators of mTORC1. eCollection 2022. 2018 Mar;138(3):657-668. doi: 10.1016/j.jid.2017.09.040. Our current understanding of, MeSH Pavitt GD, Yang W, Hinnebusch AG. Of note, the amino acid Hypusine is found in eIF5A, presumably due to a special eIF5A post-translation modification pattern. All authors read and approved the final manuscript. Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and Stress. Targeting synthetic lethal interactions between Myc and the eIF4F complex impedes tumorigenesis. Tumor Biol. Another nucleoside analog, ribavirin, was also reported to be an eIF4E-cap inhibitor and an anti-eIF4E cancer therapeutic. Elevated levels of phosphorylated 4E-BP1, which are suggestive of higher levels of eIF4F complex, were detected in advanced prostate cancer [146, 147]. Epub 2010 Sep 15. Before Aberrant expression of eIFs in human cancer. Papadopoulos E, Jenni S, Kabha E, Takrouri KJ, Yi T, Salvi N, et al. Graff JR, Konicek BW, Lynch RL, Dumstorf CA, Dowless MS, McNulty AM, et al. Expert Answer. Figure 10.7. UAC. HHS Vulnerability Disclosure, Help The significant role of PI3K in tumor development and progression makes it a promising therapeutic target [60, 61]. Bezerra MJR, Moura DMN, Freire ER, Holetz FB, Reis CRS, Monteiro TTS, Pinto ARS, Zhang N, Rezende AM, Pereira-Neves A, Figueiredo RCBQ, Clayton C, Field MC, Carrington M, de Melo Neto OP. During this process, eIFs can assist with the stabilization of the functional 80S initiation complex at the start codon and also act as regulatory targets for translation initiation. PDCD4 is reported as pro-apoptotic factor and has been suggested to possess tumor suppressor properties. The results of second-generation ASOs targeting eIF4E are encouraging, these ASOs effectively suppressed eIF4E expression in tumors, and greatly attenuate tumor burden in breast and prostate xenograft models. Brina D, Miluzio A, Ricciardi S, Biffo S. eIF6 anti-association activity is required for ribosome biogenesis, translational control and tumor progression. Taken together, these results indicate that targeting eIF4E production directly may be an attractive strategy toward effective therapy for the treatment of tumors. The major MAPK pathways involved in the regulation of protein synthesis are Ras-ERK/MAPK and Ras-p38 MAPK pathways [68]. Bound to GTP. Additionally, PRAS40 is a binding partner and suppressor of mTORC1 activity, activated AKT directly phosphorylates PRAS40, leading to its dissociation from mTORC1 and preventing its suppression of mTORC1 signaling to S6Ks and 4E-BP 1[17]. Evidence for two catalytically active kinase domains in pp90rsk. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. 4E-binding protein 1: a key molecular funnel factor in human cancer with clinical implications. However, the sustained hyper-phosphorylation of eIF2 with high doses of salubrinal treatment resulted in cancer cells apoptosis [133]. eIF4A functions in a complex termed eIF4F with two other initiation factors (eIF4E and eIF4G). Fan Q, Aksoy O, Wong RA, Ilkhanizadeh S, Novotny CJ, Gustafson WC, et al. The eIF4F complex is composed of three subunits: eIF4A, eIF4E, and eIF4G. EMBO J. In addition, eIF2-GTP-Met-tRNAiMet ternary complex is also a potential target for the inhibition of translation initiation, NSC119889 and NSC119893, brominated derivatives of fluorescein, have been found to directly target ternary complex formation and prevent the binding of tRNAiMet to eIF2 (Fig. Glycogen synthase kinase (GSK)-3 promotes p70 ribosomal protein S6 kinase (p70S6K) activity and cell proliferation. Insulin, growth factors and other stimuli activate mTORC1 signaling through binding and activating RTKs located at the membrane, following which PI3K/AKT and RAS-MAPK integrate these extracellular stimulating signals and convert them into intracellular signals. Recent findings have shown that glycogen synthase kinase (GSK) also activates p70-S6K1 by phosphorylating Ser371 in the turn motif [40]. [9] eIF3 also mediates cellular signaling through S6K1 and mTOR/Raptor to effect translational regulation.[10]. Carvajal-Carmona LG, Cazier J-B, Jones AM, Howarth K, Broderick P, Pittman A, et al. Many of substrates of ERK/MAPK and p38 MAPK have been demonstrated to control gene expression, the two major substrates, RSKs and MNKs (MAPK-interacting kinases), play a critical and direct role in the regulation of translation initiation [70, 71] (Fig. Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. Hippuristanol, pateamine A and silvestrol are inhibitors of eIF4A. Rag GTPases were identified as mediators of amino acid signaling to mTORC1. Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells. The Ras-MAPK signal pathway consists of three consecutive kinases: MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K) and MAPK. Martin-Marcos P, Nanda JS, Luna RE, Zhang F, Saini AK, Cherkasova VA, Wagner G, Lorsch JR, Hinnebusch AG. During translation initiation, eIF2-GTP is hydrolyzed to yield eIF2-GDP. Growth factors and hormones are efficient stimulators for cancer cell growth and proliferation through activating several signaling pathways to increase protein synthesis. Sheikh MS, Fornace AJJ. Tuning Specific Translation in Cancer Metastasis and Synaptic Memory: Control at the MNK-eIF4E Axis. The basic features of translation initiation in eukaryotes are shown below. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Naveau M, Lazennec-Schurdevin C, Panvert M, Mechulam Y, Schmitt E. Biochemistry. FOIA Eukaryotic initiation factors (eIF) 2alpha and 4E expression, localization, and phosphorylation in brain tumors. In comparison with transcriptional control, translational regulation of pre-existing mRNAs provides more direct, rapid and sensitive changes in intracellular levels of the encoded proteins and thus cellular adaptation during physiological and pathological conditions by rapidly reprogramming the proteome expression without the requirement for changes in RNA synthesis. The most striking feature of the RSK family is that its members have two non-overlapping and functional kinase domains, the C-terminal kinase domain (CTKD) and the N-terminal kinase domain (NTKD). Cappuzzo F, Varella-Garcia M, Rossi E, Gajapathy S, Valente M, Drabkin H, et al. Several compelling lines of evidence from animal studies indicate that the elevated levels of eIF4E phosphorylation are closely related to the development and progression of cancer [81, 151, 152]. 2022 Aug 10;10:902394. doi: 10.3389/fcell.2022.902394. 5f-h). Howard Hughes Medical Institute/United States. Grzmil M, Huber RM, Hess D, Frank S, Hynx D, Moncayo G, et al. Once attached to the mRNA, the 43S PIC is considered to scan on the 5-untranslated region (5UTR) in the 5 to 3 direction until the start codon is recognized and the 48S initiation complex formed. PMC Balabanov S, Gontarewicz A, Ziegler P, Hartmann U, Kammer W, Copland M, et al. 2021 Mar;33(5):338-348. doi: 10.1071/RD20285. Once Met-tRNAi, eIF1A and the saricinricin loop are all bound by eIF5B, GTP hydrolysis is stimulated and eIF1A and eIF5B depart, leaving a translating ribosome with Met-tRNAi in the P-site. Nat Struct Mol Biol. The https:// ensures that you are connecting to the Translation Initiation in Eukaryotes Translation initiation is the target of regulation in a number of cellular processes including development, differentiation, stress response, and neuronal function. This work was funded by the National Natural Science Foundation of China (No. It is reported that p70-S6K1 can be activated by mTORC1 and phosphoinositide-dependent kinase 1(PDK1) via the phosphorylation of Thr389 in the hydrophobic motif and Thr229 in the activation loop, respectively. eIF4E phosphorylation was suggested to be an important event in tumorigenesis and tumor progression [81]. Each subunit has multiple human isoforms and there exist additional eIF4 proteins: eIF4B and eIF4H. Black arrows and red T-bars represent stimulatory and inhibitory signals, respectively. It has been reported that phosphorylated 4E-BP1 levels in breast, ovary and prostate tumors is closely related to malignant development and poor prognosis regardless of the difference of upstream oncogenic stimulations [29]. eIF4E functions involved in translation are regulated by its availability or expression levels and its phosphorylation at Ser209. eCollection 2022. The Vam6 GEF controls TORC1 by activating the EGO complex. INTRODUCTION. Bethesda, MD 20894, Web Policies Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. It functions as a ribosomal anti-association factor in translation initiation through blocking the interaction between the 40S and 60S ribosomal subunits, namely, impeding the formation of 80S subunits without mRNA. Therefore, the molecular mechanism for the influence of S6Ks and rpS6 on translation remains unclear. Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, et al. The role of S6K1 in ER-positive breast cancer. Eukaryotic initiation factors (eIF) are proteins involved in the initiation phase of eukaryotic translation. Bar-Peled L, Sabatini DM. Exploiting the PI3K/AKT pathway for cancer drug discovery. Tomlinson IPM, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman AM, et al. Learn how and when to remove this template message, "The mechanism of eukaryotic translation initiation and principles of its regulation", "The eukaryotic translation initiation factors eIF1 and eIF1A induce an open conformation of the 40S ribosome", "Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo", "Quantitative studies of mRNA recruitment to the eukaryotic ribosome", "Molecular Cell Biology 8th ed Lodish et", "eIF3 targets cell-proliferation messenger RNAs for translational activation or repression", "mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events", "eIF5A Functions Globally in Translation Elongation and Termination", "Structural insights on the translation initiation complex: ghosts of a universal initiation complex", https://en.wikipedia.org/w/index.php?title=Eukaryotic_initiation_factor&oldid=1078859100, This page was last edited on 23 March 2022, at 18:27. 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