The DOI matches its Crossref record; 48 of the 50 references it cites were found in a registry or an index.
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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Citations
Cites
1 retracted
She, Q., Chandarlapaty, S., Ye, Q., Lobo, J. M., Haskell, K., Leander, K. R., Defeo-Jones, D., Huber, H. E., & Rosen, N. X. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003065 · Cited by 313
Self-citationRetractedChou, T.-C., & Talalay, P. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90007-4 · Cited by 7,178
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
The phosphatidylinositol 3-Kinase–AKT pathway in human cancer
Vivanco, I., & Sawyers, C. L. (2002) · Nature reviews. Cancer · doi:10.1038/nrc839 · Cited by 6,155
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
High Frequency of Mutations of the PIK3CA Gene in Human Cancers
Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A. F., Powell, S. M., Riggins, G. J., et al. (2004) · Science · doi:10.1126/science.1096502 · Cited by 3,448
Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance
McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W. T., Chang, F., Lehmann, B. D., Terrian, D. M., Milella, M., Tafuri, A., et al. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.10.001 · Cited by 2,349
Ras, PI(3)K and mTOR signalling controls tumour cell growth
Shaw, R. J., & Cantley, L. C. (2006) · Nature · doi:10.1038/nature04869 · Cited by 2,019
Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., & Gray, N. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900301200 · Cited by 1,803
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555
Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors
Mellinghoff, I. K., Wang, M. Y., Vivanco, I., Haas-Kogan, D. A., Zhu, S., Dia, E. Q., Lu, K. V., Yoshimoto, K., Huang, J. H. Y., Chute, D. J., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa051918 · Cited by 1,442
Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., Egia, A., Sasaki, A. T., Thomas, G., Kozma, S. C., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34739 · Cited by 1,381
Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., et al. (2008) · Nature Medicine · doi:10.1038/nm.1890 · Cited by 1,330
BRAF mutation predicts sensitivity to MEK inhibition
Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G. A., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., et al. (2005) · Nature · doi:10.1038/nature04304 · Cited by 1,326
Self-citationPhosphorylation and Functional Inactivation of TSC2 by Erk
Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., & Pandolfi, P. P. (2005) · Cell · doi:10.1016/j.cell.2005.02.031 · Cited by 1,268
Pause, A., Belsham, G. J., Gingras, A., Donzé, O., Lin, T.-A., Lawrence, J. C., & Sonenberg, N. (1994) · Nature · doi:10.1038/371762a0 · Cited by 1,242
Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2
Feldman, M. E., Apsel, B., Uotila, A., Loewith, R., Knight, Z. A., Ruggero, D., & Shokat, K. M. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000038 · Cited by 1,111
Regulation of cap-dependent translation by eIF4E inhibitory proteins
Richter, J. D., & Sonenberg, N. (2005) · Nature · doi:10.1038/nature03205 · Cited by 972
Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy
Wendel, H., de Stanchina, E., Fridman, J. S., Malina, A., Ray, S., Kogan, S. C., Cordon‐Cardo, C., Pelletier, J., & Lowe, S. W. (2004) · Nature · doi:10.1038/nature02369 · Cited by 956
Mutant PIK3CA promotes cell growth and invasion of human cancer cells.
Samuels, Y., Diaz, L. A., Schmidt-Kittler, O., Cummins, J. M., DeLong, L., Cheong, I., Rago, C., Huso, D. L., Lengauer, C., Kinzler, K. W., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.014 · Cited by 915
Saal, L. H., Holm, K., Maurer, M. S., Memeo, L., Su, T., Wang, X., Yu, J. S., Malmström, P.-O., MANSUKHANI, M. M., Enoksson, J., et al. (2005) · Cancer Research · doi:10.1158/0008-5472-can-04-3913 · Cited by 877
Roux, P. P., Shahbazian, D., Vu, H., Holz, M. K., Cohen, M. S., Taunton, J., Sonenberg, N., & Blenis, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700906200 · Cited by 702
Altered Growth of Human Colon Cancer Cell Lines Disrupted at Activated Ki- ras
Shirasawa, S., Furuse, M., Yokoyama, N., & Sasazuki, T. (1993) · Science · doi:10.1126/science.8465203 · Cited by 615
Self-citationGenetic Interaction Between NRAS and BRAF Mutations and PTEN/MMAC1 Inactivation in Melanoma
Tsao, H., Yang, G., Goel, V., Wu, H., & Haluska, F. G. (2004) · Journal of Investigative Dermatology · doi:10.1046/j.0022-202x.2004.22243.x · Cited by 476
Hoeflich, K. P., O'Brien, C. L., Boyd, Z. S., Cavet, G., Guerrero, S., Jung, K., Januario, T., Savage, H. M., Punnoose, E. A., Truong, T., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0317 · Cited by 474
Tumours with PI3K activation are resistant to dietary restriction
Kalaany, N. Y., & Sabatini, D. M. (2009) · Nature · doi:10.1038/nature07782 · Cited by 468
eIF4E – from translation to transformation
Mamane, Y., Petroulakis, E., Rong, L., Yoshida, K., Ler, L. W., & Sonenberg, N. (2004) · Oncogene · doi:10.1038/sj.onc.1207549 · Cited by 465
PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers
Wee, S., Jagani, Z., Xiang, K. X., Loo, A., Dorsch, M., Yao, Y.-M., Sellers, W. R., Lengauer, C., & Stegmeier, F. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4765 · Cited by 455
Phosphorylation of 4E‐BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila
Imai, Y., Gehrke, S., Wang, H.-Q., Takahashi, R., Hasegawa, K., Oota, E., & Lu, B. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.163 · Cited by 440
She, Q., Solit, D. B., Ye, Q., O'Reilly, K. E., Lobo, J. M., & Rosen, N. X. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.09.006 · Cited by 416
Self-citationLiu, Z., Hou, P., Ji, M., Guan, H., Studeman, K., Jensen, K. E., Vasko, V. V., El‐Naggar, A. K., & Xing, M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0273 · Cited by 389
Avdulov, S. V., Li, S., Michalek, V. N., Burrichter, D., Peterson, M., Perlman, D., Manivel, J. C., Sonenberg, N., Yee, D., Bitterman, P. B., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.05.024 · Cited by 341
Targeting the Eukaryotic Translation Initiation Factor 4E for Cancer Therapy
Graff, J. R., Konicek, B. W., Carter, J. H., & Marcusson, E. G. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5635 · Cited by 333
Phosphatidylinositol-3-OH Kinase or RAS Pathway Mutations in Human Breast Cancer Cell Lines
Hollestelle, A., Elstrodt, F., Nagel, J. H. A., Kallemeijn, W. W., & Schutte, M. E. M. (2007) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0263 · Cited by 325 · cited 1×
“‡ Mutations in PIK3CA and PTEN have been reported in these cell lines (Hollestelle et al., 2007; Saal et al., 2005)”
The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901
Barrett, S. D., Bridges, A. J., Dudley, D. T., Saltiel, A. R., Fergus, J. H., Flamme, C. M., Delaney, A. M., Kaufman, M., LePage, S., Leopold, W. R., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.10.054 · Cited by 289
The Splicing Factor SF2/ASF Regulates Translation Initiation by Enhancing Phosphorylation of 4E-BP1
Michlewski, G., Sanford, J. R., & Cáceres, J. F. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.013 · Cited by 280
4E-Binding Protein 1: A Key Molecular “Funnel Factor” in Human Cancer with Clinical Implications
Armengol, G., Rojo, F., Castellví, J., Iglesias, C., Cuatrecasas, M., Pons, B., Baselga, J. M., & y Cajal, S. R. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0881 · Cited by 279
PIK3CA Mutation in Colorectal Cancer: Relationship with Genetic and Epigenetic Alterations
Nosho, K., Kawasaki, T., Longtine, J. A., Fuchs, C. S., Ohnishi, M., Suemoto, Y., Kirkner, G. J., Zepf, D., Yan, L., & Ogino, S. (2008) · Neoplasia · doi:10.1593/neo.08336 · Cited by 243
The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases)
Buxadé, M. (2008) · Frontiers in bioscience · doi:10.2741/3086 · Cited by 185
Herbert, T. P., Tee, A. R., & Proud, C. G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110367200 · Cited by 183
Simi, L., Pratesi, N., Vignoli, M., Sestini, R., Cianchi, F., Valanzano, R., Nobili, S., Mini, E., Pazzagli, M., & Orlando, C. (2008) · American Journal of Clinical Pathology · doi:10.1309/lwdy1axhxuulnvhq · Cited by 166
Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs
Rong, L., Livingstone, M., Sukarieh, R., Petroulakis, E., Gingras, A., Crosby, K., Smith, B., Polakiewicz, R. D., Pelletier, J., Ferraiuolo, M. A., et al. (2008) · RNA · doi:10.1261/rna.950608 · Cited by 139
Ericson, K., Gan, C. M., Cheong, I., Rago, C., Samuels, Y., Velculescu, V. E., Kinzler, K. W., Huso, D. L., Vogelstein, B., & Papadopoulos, N. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914018107 · Cited by 122
Yu, K., Toral‐Barza, L., Shi, C., Zhang, W., & Zask, A. (2008) · Cancer Biology & Therapy · doi:10.4161/cbt.7.2.5334 · Cited by 92
Bilodeau, M. T., Balitza, A. E., HOFFMAN, J. M. J., Manley, P. J., Barnett, S. F., Defeo-Jones, D., Haskell, K., Jones, R. E., Leander, K. R., Robinson, R., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.04.074 · Cited by 83
Cherrin, C., Haskell, K., Howell, B., Jones, R., Leander, K. R., Robinson, R., Watkins, A., Bilodeau, M. T., HOFFMAN, J. M. J., Sanderson, P. E. J., et al. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.9.7.11100 · Cited by 61
Self-citationThe Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways
Polunovsky, V. A., & Bitterman, P. B. (2006) · RNA Biology · doi:10.4161/rna.3.1.2718 · Cited by 57
Jacobson, B. A., Alter, M. D., Kratzke, M. G., Frizelle, S. P., Zhang, Y., Peterson, M. S., Avdulov, S. V., Mohorn, R. P., Whitson, B. A., Bitterman, P. B., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2879 · Cited by 49
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Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509
“Interestingly, the contribution of S6K1 and S6 to the oncogenic action of ERK and/or Akt appears limited, indicating that the signaling branches controlling protein synthesis downstream of mTORC1 are not equally required in oncogenesis (Hsieh et al., 2010; She et al., 2010).”
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Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
“Consistent with this, a variety of Aktand Erk-driven cancer cell lines are dependent on 4EBP phosphorylation, and the ratio of 4EBP to eIF4E expression correlates well with their sensitivity to mTOR inhibitors (Alain et al., 2012; She et al., 2010).”
BackgroundmTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941
“; conversely, expression of a non-phosphorylatable, constitutively active 4E-BP1 suppressed the growth of tumours driven by concomitant PI3K and KRAS mutation”
BackgroundPI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Glaviano, A., Foo, A. S. C., Lam, H. Y., Yap, K. C. H., Jacot, W., Jones, R. H., Eng, H., Nair, M. G., Makvandi, P., Geoerger, B., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01827-6 · Cited by 2,138
The functions and regulation of the PTEN tumour suppressor
Song, M. S., Salmena, L., & Pandolfi, P. P. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3330 · Cited by 1,926
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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