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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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“This is thought to be due to the interaction between the MEK–ERK and PI3K–Akt pathways (42, 43).”
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“Studies of β-adrenergic signaling cascades in mouse hippocampal tissue indicate that both mTOR and MAPK pathways must be concurrently active in order for translation to occur”
BackgroundKhalili, J. S., Yu, X., Wang, J., Hayes, B. C., Davies, M. A., Lizee, G. A., Esmaeli, B., & Woodman, S. E. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3227 · Cited by 147
“, colon carcinomas with both KRAS and PI3KCA mutations)(27).”
Morkel, M., Riemer, P., Bläker, H., & Sers, C. (2015) · Oncotarget · doi:10.18632/oncotarget.4750 · Cited by 146
“In this regard, it is important that the PIK3CA-AKT-mTOR axis is frequently activated either by loss of PTEN or activation of PIK3CA in CRC, independent of the KRAS or BRAF status [132].”
BackgroundInfluentialAkhavan, D., Pourzia, A. L., Nourian, A. A., Williams, K. J., Nathanson, D. A., Babić, I., Villa, G. R., Tanaka, K., Nael, A., Yang, H., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0502 · Cited by 143
“a parallel pathway (38) by which ERK signaling also suppresses PDGFRβ.”
Antitumor Activity in RAS -Driven Tumors by Blocking AKT and MEK
Tolcher, A. W., Khan, K. H., Ong, M., Banerji, U., Papadimitrakopoulou, V. A., Gandara, D. R., Patnaik, A., Baird, R. D., Olmos, D., Garrett, C. R., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1901 · Cited by 140
“Numerous preclinical models have suggested that KRASmutant tumors require cotargeting of the Ras/Raf/MEK/ERK and PI3K/AKT pathways due to multiple points of cross-talk, negative feedback, and redundancy (6, 7).”
BackgroundRegulation of PTEN translation by PI3K signaling maintains pathway homeostasis
Mukherjee, R., Vanaja, K. G., Boyer, J. A., Gadal, S., Solomon, H., Chandarlapaty, S., Levchenko, A., & Rosen, N. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.033 · Cited by 135
“This mutant is unphosphorylatable and binds constitutively to eIF4E causing inhibition of cap-dependent translation (Cai et al., 2014; She et al., 2010).”
BackgroundSelf-citationInhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours
Wu, Z. R., Yan, L., Liu, Y. T., Cao, L., Guo, Y., Zhang, Y., Yao, H., Cai, L., Shang, H. B., Rui, W. W., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06853-3 · Cited by 135
mTORC1 is essential for leukemia propagation but not stem cell self-renewal
Hoshii, T., Tadokoro, Y., Naka, K., Ooshio, T., Muraguchi, T., Sugiyama, N., Soga, T., Araki, K., Yamamura, K., & Hirao, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62279 · Cited by 140
“Although previous studies reported that inhibition of 4E-BP phosphorylation is associated with the induction of apoptosis in tumors (39, 40), it was assumed that other molecules downstream of mTORC1 cooperatively contribute to AML propagation.”
ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling
Winter, J. N., Jefferson, L. S., & Kimball, S. R. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00504.2010 · Cited by 135
“A recent study (44) demonstrated that in tumor cell lines in which independent mutations occur in both the catalytic subunit of phosphoinositide-3 kinase (PI3K) and B-Raf, inhibition of either the Akt or ERK pathway alone is ineffective in repressing cell proliferation.”
BackgroundS6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1
Ben-Hur, V., Denichenko, P., Siegfried, Z., Maimon, A., Krainer, A. R., Davidson, B., & Karni, R. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.11.020 · Cited by 133
“We next examined, using two complementary strategies, if this activation is required for their oncogenic activities: 1) Inhibition of mTORC1 by the pharmacological inhibitor rapamycin and 2) expression of a phosphorylation-defective 4E-BP1 which is mutated in its phosphorylation sites and cannot dissociate from eIF4E…”
BackgroundMethodInfluentialCDK1 substitutes for mTOR kinase to activate mitotic cap-dependent protein translation
Shuda, M., Velásquez, C., Cheng, E., Cordek, D. G., Kwun, H. J., Chang, Y., & Moore, P. S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505787112 · Cited by 131
“Mounting evidence suggests that dysregulated cap-dependent translation from aberrant PI3K–Akt–mTOR and MEF–RAF–MEK–ERK signaling contributes to cancer cell transformation (3, 52).”
BackgroundAkt: a key transducer in cancer
Tsai, P., Lai, Y., Manne, R., Tsai, Y.-S., Sarbassov, D. D., & Lin, H. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00860-9 · Cited by 138
“Similarly, overexpression of mutant 4E-BP1 inhibits PI3KCA and K-Ras mutant tumor growth in the xenograft tumor model [81].”
BackgroundCYP1A1 Regulates Breast Cancer Proliferation and Survival
Rodriguez, M., & Potter, D. A. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0675 · Cited by 125
“These reductions in phosphorylation correlate with downstream inhibition of the protein synthesis regulator P70S6K (23, 24).”
BackgroundInfluentialFaber, A. C., Coffee, E. M., Costa, C., Dastur, A., Ebi, H., Hata, A. N., Yeo, A. T., Edelman, E. J., Song, Y., Tam, A. T., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0315 · Cited by 124
The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53
Lee, S.-O., Andey, T. A., Jin, U.-H., Kim, K., Sachdeva, M. S., & Safe, S. H. (2011) · Oncogene · doi:10.1038/onc.2011.504 · Cited by 122
“The phosphorylated forms of 4E-BP1 and p70S6K are key downstream targets of mTORC1 that regulate initiation and translation of multiple genes, such as cyclin D1 and cyclin A, that are critical for normal cell growth, and in a cancer context many of the the 4E-BP1- and p70S6K-regulated genes are prooncogenic (Hay and S…”
Hernandez, B., Adissu, H. A., Wei, B., Michael, H., Merlino, G. T., & Simpson, R. M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020394 · Cited by 124
“Inhibition of both pathways may be beneficial due to significant crosstalk and redundancy between the pathways [8,80].”
BackgroundCurrent State and Future Challenges for PI3K Inhibitors in Cancer Therapy
Sirico, M., D’Angelo, A., Gianni, C., Casadei, C., Merloni, F., & De Giorgi, U. (2023) · Cancers · doi:10.3390/cancers15030703 · Cited by 121
“It can potentially treat a wide range of solid and hematologic malignancies as a monotherapy or in combination, both in vivo and in vitro [86].”
BackgroundYellen, P., Saqcena, M., Salloum, D., Feng, J., Preda, A., Xu, L., Rodrik-Outmezguine, V. S., & Foster, D. A. (2011) · Cell Cycle · doi:10.4161/cc.10.22.18124 · Cited by 117
Signaling cross-talk in the resistance to HER family receptor targeted therapy
Yamaguchi, H., Chang, S. H., Hsu, J. L., & Hung, M. (2013) · Oncogene · doi:10.1038/onc.2013.74 · Cited by 118
Genomic Complexity and AKT Dependence in Serous Ovarian Cancer
Hanrahan, A. J., Schultz, N. D., Westfal, M. L., Sakr, R. A., Giri, D. D., Scarperi, S., Janikariman, M., Olvera, N., Stevens, E. V., She, Q., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0170 · Cited by 118
Self-citationAmino acid management in cancer
Tsun, Z.-Y., & Possemato, R. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.08.002 · Cited by 120
Anti-oncogenic potential of the eIF4E-binding proteins
Martineau, Y., Azar, R., Bousquet, C., & Pyronnet, S. (2012) · Oncogene · doi:10.1038/onc.2012.116 · Cited by 125
Zhang, X., Hua, R., Wang, X., Huang, M., Gan, L., Wu, Z., Zhang, J., Wang, H., Cheng, Y., Li, J., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6890 · Cited by 109
“Furthermore, the expression of p-ERK and p-AKT, which have been reported to effect tumorigenesis in tandem [40, 41] were both highly expressed together in gastric CSCs isolated in this study.”
BackgroundMissailidis, D., Annesley, S. J., Allan, C. Y., Sanislav, O., Lidbury, B. A., Lewis, D. P., & Fisher, P. R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031074 · Cited by 107
“Together with S6 kinase (S6K), 4E-BP1 mediates the roles of TORC1 in regulating translation in the cytosol of mRNAs encoding major functional groups of proteins [40-42].”
BackgroundSee, W. L., Tan, I., Mukherjee, J., Nicolaides, T. P., & Pieper, R. O. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0334 · Cited by 106
“Alternatively, MEK inhibitor– based trials could be designed to include a PI3K/mTOR inhibitor, addition of which enhances MEK inhibitor sensitivity (13, 14, 16, 36, 38, 39), and may target a broader GBM population.”
BackgroundActivating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis
Charles, R., Silva, J. M., Iezza, G., Phillips, W. A., & McMahon, M. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0158-t · Cited by 104
“on the phosphorylation of ribosomal protein S6 (rpS6) and 4E-BP1, that latter of which directly regulates Cap-dependent protein translation [17].”
BackgroundEffect of Capivasertib in Patients With an AKT1 E17K-Mutated Tumor
Kalinsky, K. M., Hong, F., McCourt, C. K., Sachdev, J. C., Mitchell, E. P., Zwiebel, J. A., Doyle, L. A., McShane, L. M., Li, S., Gray, R. J., et al. (2020) · JAMA Oncology · doi:10.1001/jamaoncol.2020.6741 · Cited by 102
Targeting mTOR network in colorectal cancer therapy
Wang, X. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i15.4178 · Cited by 104
S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer
Nawroth, R., Stellwagen, F., Schulz, W. A., Stoehr, R., Hartmann, A., Krause, B. J., Gschwend, J. E., & Retz, M. M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027509 · Cited by 99
“events of the PI3K and MAPK pathway in tumors [15].”
BackgroundInfluentialTanaka, H., Yoshida, M., Tanimura, H., Fujii, T., Sakata, K., Tachibana, Y., Ohwada, J., Ebiike, H., Kuramoto, S., Morita, K., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2882 · Cited by 97
Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer
Donnella, H. J., Webber, J. T., Levin, R. S., Camarda, R., Momcilovic, O., Bayani, N., Shah, K. N., Korkola, J. E., Shokat, K. M., Goga, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0081-9 · Cited by 90
“This may be due to the convergence of both the PI3K and MAPK pathways on protein synthesis 38,39 .”
Sun, H., Yang, W., Tian, Y., Zeng, X., Zhou, J., Mok, M. T. S., Tang, W., Feng, Y., Xu, L., Chan, A. W. H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07402-8 · Cited by 93
He, K., Zheng, X., Li, M., Zhang, L., & Yu, J. (2015) · Oncogene · doi:10.1038/onc.2015.79 · Cited by 93
“S3C-D), supporting mTOR-independent 4E-BP1 phosphorylation in CRC cells (22).”
mRNA Translation and Energy Metabolism in Cancer: The Role of the MAPK and mTORC1 PathwaysPreprint
Topisirović, I., & Sonenberg, N. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010785 · Cited by 96
“Accordingly, combined inhibition of MAPK and PI3K/AKT completely and sustainably inhibits the phosphorylation of 4E-BPs, which is paralleled by tumor growth reduction (She et al. 2010).”
BackgroundDucker, G. S., Atreya, C. E., Simko, J. P., Hom, Y. K., Matli, M. R., Benes, C. H., Hann, B. C., Nakakura, E. K., Bergsland, E. K., Donner, D. B., et al. (2013) · Oncogene · doi:10.1038/onc.2013.92 · Cited by 91
Pek, M., Yatim, S. M. J. M., Chen, Y., Li, J., Gong, M., Jiang, X., Zhang, F., Zheng, J., Wu, X., & Yu, Q. (2017) · Oncogene · doi:10.1038/onc.2017.120 · Cited by 86
Bousquet, C., Lasfargues, C., Chalabi‐Dchar, M., Moatassim-Billah, S., Susini, C., Vezzosi, D., Caron, P. J., & Pyronnet, S. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2088 · Cited by 87
“4E-BP1 was demonstrated to be an essential factor that transduces oncogenic signals downstream of the AKTmTOR and ERK pathways (55, 56).”
BackgroundMYC Cooperates with AKT in Prostate Tumorigenesis and Alters Sensitivity to mTOR Inhibitors
Clegg, N. J., Couto, S. S., Wongvipat, J., Hieronymus, H., Carver, B. S., Taylor, B. S., Ellwood‐Yen, K., Gerald, W. L., Sander, C., & Sawyers, C. L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017449 · Cited by 92
“Furthermore, phosphorylation of 4EBP1 was unimpaired by mTOR inhibition in these mice (but rather increased, possibly due to feedback activation of the MEK/ERK-pathway [44]).”
BackgroundSynthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors
Liu, T., Nair, S. J., Lescarbeau, A., Belani, J. D., Peluso, S., Conley, J., Tillotson, B. P., O’Hearn, P. J., Smith, S. A., Slocum, K. L., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3011542 · Cited by 86
Synergistic Action of a RAF Inhibitor and a Dual PI3K/mTOR Inhibitor in Thyroid Cancer
Jin, N. Y., Jiang, T., Rosen, D. M., Nelkin, B. D., & Ball, D. W. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0933 · Cited by 85
“The mechanisms reported to underlie this synergy include downstream convergence of translational control of prosurvival signaling (29) and modulation of expression of proapoptotic and antiapoptotic BH3 proteins (30).”
BackgroundDNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR
Micevic, G., Muthusamy, V., Damsky, W., Theodosakis, N., Liu, X., Meeth, K. M., Wingrove, E., Santhanakrishnan, M., & Bosenberg, M. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.010 · Cited by 86
“Modulation of PI3K and downstream signaling effectors including AKT, mTORC1, and/or mTORC2 can have marked effects on melanoma formation (Damsky et al., 2015; Damsky et al., 2011; Karbowniczek et al., 2008; She et al., 2010).”
Background
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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