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4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors
Open accessAbstract
PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.
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“This is consistent with previous reports and with our previous finding that anti-proliferative efficacy requires dephosphorylation of 4E-BP1 and its consequent inhibition of cap-dependent translation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
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“We have previously shown that combined inhibition of MEK and AKT attenuates the growth of KRAS tumors and that this is dependent on suppression of 4E-BP1 phosphorylation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
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“We have previously shown that the PI3K/AKT/mTOR and RAS/RAF/ERK pathways converge on key cellular processes, including Cyclin D-Cdk4/6 activation and cap-dependent translation and that both pathways must be inhibited to affect tumor growth or survival15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
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“We have previously shown that AKT and MEK inhibition cooperate to inhibit 4E-BP1 phosphorylation and that dephosphorylation of 4E-BP1 is required for the anti-tumor activity of the combination15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
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“These data are consistent with our previous findings that 4E-BP1 is a convergent target of PI3K/AKT/mTOR and RAF/MEK/ERK pathways and integrates their function at the level of regulation of cap-dependent translation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
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“Nevertheless, these data are consistent with our previous findings that inhibition of the growth of tumors in which ERK and PI3K/mTOR signaling are dysregulated requires inhibition of both pathways15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
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“We have previously shown that several downstream processes are under the control of both ERK and PI3K/mTOR signaling and that their effective inhibition requires inhibition of both pathways15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
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“This finding is consistent with a report suggesting that other KRAS-regulated pathways, in addition to MEK-ERK, contribute to phosphorylation of 4EBP1(45).”
From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [45]
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Items 301–400 of 401
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“…andcap-dependentmRNAtranslation — which represent an established convergence point of integrated ERK/MAPK and PI3K/AKT/mTOR signaling 33 — and the asymmetric expressionpatterns between these clusters suggest that intrinsic feedback events are rendered ineffective in the setting of…”
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All Roads Lead to the Ribosome
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“These pathways can be inhibited separately, but in this issue of Cancer Cell, She et al. elegantly reveal that it may be possible to target both simultaneously through a common down- stream effector (She et al., 2010).”
BackgroundSTAT3‐mediated MLST8 gene expression regulates cap‐dependent translation in cancer cells
Lee, H., Chin, H., Kim, H., Jung, H.-S., & Lee, D. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12735 · Cited by 9
Biomarkers of everolimus efficacy in breast cancer therapy
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“Differential sensitivity relates to a differential ability of mTOR to phosphorylate various physiologic substrates.24 Phosphorylation of p70S6 K is effectively inhibited by these drugs, while persistent 4EBP1 phosphorylation is insensitive to rapalogs.25 Insensitivity of 4EBP1 inhibition may be related to the fact tha…”
BackgroundInfluentialCharacterization of polyploidy in cancer: Current status and future perspectives
Ghosh, S., Choudhury, D., Ghosh, D., Mondal, M., Singha, D., & Malakar, P. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.131706 · Cited by 11
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“Activated mTORC1 phosphorylates 4E-BP1, leading to the formation of the eIF4F complex and the initiation of cap-dependent translation.(6) Since it was found that INPP4B increased mTORC1 activity, the investigators determined whether INPP4B enhanced cap-dependent translation in CRC cells.”
BackgroundLum, M. A., Jonas, K. A., Parmar, S., Black, A. R., O’Connor, C. M., Dobersch, S., Yamamoto, N., Robertson, T. M., Schutter, A., Giambi, M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci176093 · Cited by 7
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“A study by She et al, further suggests that 4E-BP1 mediates the effects of mutational activated PI3K-AKT and RAS-ERK signaling [79].”
BackgroundTumor antigen presentation and the associated signal transduction during carcinogenesis
Naskar, S., Sriraman, N., Sarkar, A., Mahajan, N., & Sarkar, K. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155485 · Cited by 7
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“In view of the importance of the 4E-BPs for the control of proliferation of untransformed cells, as well as the well known role of dysregulation of the eIF4E/4E-BP system in cancer progression [59,60], it would be of interest to determine whether the sensitivity of protein synthesis and cell proliferation to mTOR inhi…”
BackgroundTargeted therapy sensitivity and resistance in solid malignancies
Jokinen, E. (2014) · Cited by 6
Fujinaga, A., Hirashita, T., Hirashita, Y., Sakai, K., Kawamura, M., Masuda, T., Endo, Y., Ohta, M., Murakami, K., & Inomata, M. (2023) · BMC Gastroenterology · doi:10.1186/s12876-023-02815-2 · Cited by 6
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“Phosphorylation of 4E-BP1 is not only regulated by mTORC1, but also by ERK signaling [43,46], suggesting the crosstalk between PI3K/mTOR pathway and MAPK pathway.”
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“Overexpression of Clast4 delays cell proliferation Because 4E-BP binds eIF4E to hinder translation initiation, and the expression level of 4E-BP correlates with oncogenic activation [17], we checked whether the overexpression of Clast4 influences cell proliferation.”
BackgroundAkt inhibitors in cancer therapy
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“Dephosphorylation of 4E-BP1 has been shown to be an important biomarker for predicting cancer cell response to anticancer therapies [35] and for reducing cell invasion by, for instance, inhibiting the epithelial–mesenchymal transition (EMT) [36].”
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“…± 4.05 µ M for MDA-MB-231 and 1.94 ± 1.33 µ M for HS578T cells (Figure 3C). eIF4E-binding protein 1 (4E-BP1), an oncogenic convergent target integrating the MEK/ERK and PI3K/AKT pathways [47], showed reduced phosphorylation at T37/46 upon fedratinib treatment in a dose-dependent manner (Figure 3D).”
InfluentialFrequent 4EBP1 Amplification Induces Synthetic Dependence on FGFR Signaling in Cancer
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“During mTOR/AKT/PI3K activation, 4E-BP1 is phosphorylated, which frees and activates eIF4E and stimulates translation and tumor growth in vivo [9].”
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Targeting eukaryotic protein translation in mesothelioma
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“Phosphorylation and activation of eIF4E by the mTOR kinase is a powerful downstream signal for cell growth mediated by activation of cell surface tyrosine kinases (8,9).”
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“Recently, clinical findings showed that the expression of high levels of phosphorylated 4E-BP1 were associated with poor prognosis in several tumor types, independent of specific upstream oncogenic alterations.(11,12) Tam et al.”
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“69 In keeping with the possibility that 4EBP1 also mediates the AKT leg of the mTOR signaling pathway, a kinase activity speci fi c to Ser65 and Thr70 on 4EBP1 was reported to be liberated from an mTOR immunoprecipitate, suggesting the presence of a different kinase.”
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Metadata
- Authors
- She, Q.-B., Halilovic, E., Ye, Q., Zhen, W., Shirasawa, S., Sasazuki, T., Solit, D. B., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Fukuoka University (JP)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 18
- Issue
- 1
- Pages
- 39-51
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3286650
- OpenAlex
- W2084875329
- Cited by
- 400
- References
- 50
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 16 · 2023: 12 · 2022: 21 · 2021: 17 · 2020: 11 · 2019: 16 · 2018: 23 · 2017: 26 · 2016: 22 · 2015: 33 · 2014: 45 · 2013: 42 · 2012: 49
- FWCI
- 18.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA129243, P01CA094060)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- 4E-BP1, Akt signaling, ERK signaling, PIK3CA mutation, PTEN loss, cap-dependent translation, translational repressor, MEK inhibitors, AKT inhibitors, combination therapy synergy, oncogene activation
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Colonic Neoplasms, Female, Humans, Mice, Nude, Mutation, Phosphoproteins, RNA, Messenger, Protein Biosynthesis, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Survival Rate, Apoptosis, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Extracellular Signal-Regulated MAP Kinases, Adaptor Proteins, Signal Transducing, Cell Proliferation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Class I Phosphatidylinositol 3-Kinases
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