Activation of translation initiation factor eIF2B by insulin requires phosphatidyl inositol 3‐kinase

Welsh, Gavin I.; Stokes, Christa M; Wang, Xuemin; Sakaue, Hiroshi; Ogawa, Wataru; Kasuga, Masato; Proud, Christopher G.

doi:10.1016/s0014-5793(97)00579-6

Cited by 96 publications

(84 citation statements)

References 42 publications

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“…We performed a full analysis of limiting factors eIF4F and eIF2. eIF2-mediated ternary complex formation is negatively regulated by phosphorylation of eIF2␣ subunit activated by several stimuli (18,(20)(21)(22)(23)(24)(25). Deprivation of matrix attachment strongly induced phosphorylation of eIF2␣, but left eIF4F formation almost unchanged (Fig.…”

Section: Pi3k Activation Does Not Restore Translation In Attachment-dmentioning

confidence: 93%

“…In mammals, eIF2-␣ mediated down-regulation of translation is under the control of four different eIF2-␣ kinases and occurs in response to negative conditions for growth as diverse as amino acid deprivation (17), iron deficiency (18), heat shock and viral infection (19), endoplasmic reticulum stress (20,21), and UV exposure (22,23). Additionally, eIF2B activity is modulated by a PI3K-glycogen synthase kinase-3 pathway (24,25). Thus, the combination of different pathways converging to the translational machinery results in quantitative and qualitative changes of the mRNAs to be translated.…”

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confidence: 99%

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Fibronectin controls cap-dependent translation through β1 integrin and eukaryotic initiation factors 4 and 2 coordinated pathways

Gorrini

Loreni

Gandin

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Fibronectin (FN) is a major matrix protein involved in multiple processes. Little is known about how adhesion to FN affects the translational machinery. We show that in fibroblasts adhesion to FN triggers translation through the coordinated regulation of eukaryotic initiation factors (eIFs) 4F and 2 and is impaired by blocking ␤1 integrin engagement. FN-stimulated translation has unique properties: (i) it is highly sensitive to the inhibition of phosphatidylinositol 3-kinase (PI3K), but not to the inhibition of mammalian target of rapamycin, downstream of PI3K; (ii) there is no synergy between serum-stimulated translation and FN-dependent translation; (iii) FN-dependent translation, unlike growth factor-stimulated translation, does not lead to increased translocation of 5 terminal oligopyrimidine tract mRNAs to polysomes; and (iv) cells devoid of attachment to matrix show an impairment of initiation of translation accompanied by phosphorylation of eIF2␣, which cannot be reverted by active PI3K. These findings indicate that integrins may recruit the translational machinery in a unique way and that FN-dependent translation cannot be blocked by mammalian target of rapamycin inhibition.initiation ͉ mammalian target of rapamycin (mTOR) ͉ terminal oligopyrimidine tract mRNAs I n eukaryotic cells, the control of translation contributes to the definition of the spectrum of expressed proteins (1, 2). Extracellular signals modulate translation by signaling cascades that converge on initiation, the main rate-limiting step of translation. Initiation is controlled by multiple proteins (3). Adhesion to matrix is, potentially, a powerful regulator of translation because it provides positional clues and activates a signaling cascade.Briefly, at initiation, two regulatory steps involving eukaryotic initiation factor (eIF) 4F (4) and eIF2 (5) have been characterized. eIF4F complex formation assists translation of capped mRNAs with polyadenylated 3Ј UTR. eIF4F is a multisubunit complex formed by (i) eIF4E, which binds the 5Ј cap structure (m 7 GpppN), (ii) eIF4A, an ATP-dependent RNA helicase, and (iii) eIF4G, a scaffold protein that binds eIF4E, eIF4A, and the poly(A) binding protein PABP (4, 6). Formation of eIF4F is regulated by sequestering eIF4E through the binding to negative regulators 4E-BPs. Phosphorylation of 4E-BP1, in response to growth factors, releases eIF4E from the inactive 4E-BP1͞eIF4E complex and allows its binding to eIF4G to form active eIF4F (7,8). The best-characterized pathway upstream of eIF4F formation is formed by the phosphatidylinositol 3-kinase (PI3K)-Aktmammalian target of rapamycin (mTOR) cascade; mTOR phosphorylates 4E-BPs, activating formation of the eIF4F complex (9-11). A specific class of mRNAs defined as TOPs (terminal oligopyrimidine tracts) is translated after stimulation of the PI3K-mTOR pathway. 5Ј TOPs code for ribosomal proteins and translation factors (12)(13)(14). TOP mRNA translation is therefore important in cell growth. Additional regulation of eIF4F complex may involve eIF4E phospho...

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Section: Pi3k Activation Does Not Restore Translation In Attachment-dmentioning

confidence: 93%

mentioning

confidence: 99%

Fibronectin controls cap-dependent translation through β1 integrin and eukaryotic initiation factors 4 and 2 coordinated pathways

Gorrini

Loreni

Gandin

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus another PI 3-kinase-linked signalling pathway must be responsible for this, and this would be entirely consistent with the operation of the pathway depicted in Scheme 4. Welsh et al [84] have recently shown that PI 3-kinase is required for the activation of eIF2B, using both specific inhibitors of this enzyme and dominant negative mutants of the p85 subunit of PI 3-kinase. In contrast, neither MAP kinase nor the FRAP pathway seem to be required for the activation of eIF2B.…”

Section: Scheme 4 Signalling Pathway Likely To Be Involved In the Regmentioning

confidence: 99%

Molecular mechanisms for the control of translation by insulin

Proud

Denton

1997

Biochemical Journal

242

162

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Insulin acutely stimulates protein synthesis in mammalian cells, and this involves activation of the process of mRNA translation. mRNA translation is a complex multi-step process mediated by proteins termed translation factors. Several translation factors are regulated in response to insulin, often as a consequence of changes in their states of phosphorylation. The initiation factor eIF4E binds to the cap structure at the 5ʹ-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eIF4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. Insulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especially important for the control of the translation of specific mRNAs whose 5ʹ-untranslated regions (5ʹ-UTRs) are rich in secondary structure. Translation of another class of mRNAs, those with 5ʹ-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Overall stimulation of translation may involve activation of initiation factor eIF2B, which is required for all initiation events. This effect is dependent upon phosphatidylinositol 3-kinase and may involve the inactivation of glycogen synthase kinase-3 and consequent dephosphorylation of eIF2B, leading to its activation. Peptide-chain elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, probably as a consequence of the insulin-induced reduction in eEF2 kinase activity. Thus multiple signalling pathways acting on different steps in translation are involved in the activation of this process by insulin and lead both to general activation of translation and to the selective regulation of specific mRNAs.

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“…IGF-1 regulates the Akt/mTOR and the Akt/GSK-3␤ signaling pathways, which are involved in the skeletal muscle hypertrophy process by activating downstream regulators of protein initiation and translation. 19 In the elderly when compared to younger subjects, a reduction on the total protein content of several protein initiation and translation targets, such as mTOR, p70s6k, 4E-BP1, and eIF2B, all of which are either direct or indirect targets of Akt, [20][21][22] have been observed. 23 Additionally, the sensitivity and responsiveness of these proteins to stimulation via administration of essential amino acids are reduced in older subjects.…”

Section: Introduction Smentioning

confidence: 99%

Human Sarcopenia Reveals an Increase in SOCS-3 and Myostatin and a Reduced Efficiency of Akt Phosphorylation

Léger

Derave

Bock

et al. 2008

Rejuvenation Research

235

175

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Age-related skeletal muscle sarcopenia is linked with increases in falls, fractures, and death and therefore has important socioeconomic consequences. The molecular mechanisms controlling age-related muscle loss in humans are not well understood, but are likely to involve multiple signaling pathways. This study investigated the regulation of several genes and proteins involved in the activation of key signaling pathways promoting muscle hypertrophy, including GH/STAT5, IGF-1/Akt/GSK-3␤/4E-BP1, and muscle atrophy, including TNF␣/ SOCS-3 and Akt/FKHR/atrogene, in muscle biopsies from 13 young (20 ؎ 0.2 years) and 16 older (70 ؎ 0.3 years) males. In the older males compared to the young subjects, muscle fiber cross-sectional area was reduced by 40-45% in the type II muscle fibers. TNF␣ and SOCS-3 were increased by 2.8 and 1.5 fold, respectively. Growth hormone receptor protein (GHR) and IGF-1 mRNA were decreased by 45%. Total Akt, but not phosphorylated Akt, was increased by 2.5 fold, which corresponded to a 30% reduction in the efficiency of Akt phosphorylation in the older subjects. Phosphorylated and total GSK-3␤ were increased by 1.5 and 1.8 fold, respectively, while 4E-BP1 levels were not changed. Nuclear FKHR and FKHRL1 were decreased by 73 and 50%, respectively, with no changes in their atrophy target genes, atrogin-1 and MuRF1. Myostatin mRNA and protein levels were significantly elevated by 2 and 1.4 fold. Human sarcopenia may be linked to a reduction in the activity or sensitivity of anabolic signaling proteins such as GHR, IGF-1, and Akt. TNF␣, SOCS-3, and myostatin are potential candidates influencing this anabolic perturbation. 163

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Activation of translation initiation factor eIF2B by insulin requires phosphatidyl inositol 3‐kinase

Cited by 96 publications

References 42 publications

Fibronectin controls cap-dependent translation through β1 integrin and eukaryotic initiation factors 4 and 2 coordinated pathways

Fibronectin controls cap-dependent translation through β1 integrin and eukaryotic initiation factors 4 and 2 coordinated pathways

Molecular mechanisms for the control of translation by insulin

Human Sarcopenia Reveals an Increase in SOCS-3 and Myostatin and a Reduced Efficiency of Akt Phosphorylation

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