Inhibition of B56-containing Protein Phosphatase 2As by the Early Response Gene IEX-1 Leads to Control of Akt Activity
Open accessAbstract
The importance of PP2A in the regulation of Akt/PKB activity has long been recognized but the nature of the holoenzyme involved and the mechanisms controlling dephosphorylation are not yet known. We identified IEX-1, an early gene product with proliferative and survival activities, as a specific inhibitor of B56 regulatory subunit-containing PP2A. IEX-1 inhibits B56-PP2A activity by allowing the phosphorylation of B56 by ERK. This leads to sustained ERK activation. IEX-1 has no effect on PP2A containing other B family subunits. Thus, studying IEX-1 contribution to signaling should help the discovery of new pathways controlled by B56-PP2A. By using overexpression and RNA interference, we show here that IEX-1 increases Akt/PKB activity in response to various growth factors by preventing Akt dephosphorylation on both Thr(308) and Ser(473) residues. PP2A-B56beta and gamma subunits have the opposite effect and reverse IEX-1-mediated Akt activation. The effect of IEX-1 on Akt is ERK-dependent. Indeed: (i) a IEX-1 mutant deficient in ERK binding had no effect on Akt; (ii) ERK dominant-negative mutants reduced IEX-1-mediated increase in pAkt; (iii) a B56beta mutant that cannot be phosphorylated in the ERK.IEX-1 complex showed an enhanced ability to compete with IEX-1. These results identify B56-containing PP2A holoenzymes as Akt phosphatases. They suggest that IEX-1 behaves as a general inhibitor of B56 activity, enabling the control of both ERK and Akt signaling downstream of ERK.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
B56c negatively regulates Akt kinase phosphorylation.
“negatively regulates Akt kinase phosphorylation [25,29]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [29]
Cites
1 retracted
Chen, W., Arroyo, J. D., Timmons, J. C., Possemato, R., & Hahn, W. C. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1103 · Cited by 159 · see citing works
RetractedPhosphorylation 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 · see citing works
Alessi, D., James, S., Downes, C., Holmes, A. B., Gaffney, P., Reese, C., & Cohen, P. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00122-9 · Cited by 3,047 · see citing works
Oncogenic pathway signatures in human cancers as a guide to targeted therapies
Bild, A., Yao, G., Chang, J. T., Wang, Q., Potti, A., Chasse, D. A. D., Joshi, M.-B., Harpole, D. H., Lancaster, J. M., Berchuck, A., et al. (2005) · Nature · doi:10.1038/nature04296 · Cited by 2,032 · see citing works
Janssens, V., & Goris, J. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3530417 · Cited by 1,890 · see citing works
Janssens, V., & Goris, J. (2001) · Biochemical Journal · doi:10.1042/bj3530417 · Cited by 1,392 · see citing works
Phosphorylation 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 · see citing works
Phosphorylation and Regulation of Raf by Akt (Protein Kinase B)
Zimmermann, S., & Moelling, K. (1999) · Science · doi:10.1126/science.286.5445.1741 · Cited by 1,088 · see citing works
Stephens, L., Anderson, K. E., Stokoe, D., Erdjument‐Bromage, H., Painter, G. F., Holmes, A. B., Gaffney, P. R. J., Reese, C. B., McCormick, F. P., Tempst, P., et al. (1998) · Science · doi:10.1126/science.279.5351.710 · Cited by 1,061 · see citing works
An Akt/β-Arrestin 2/PP2A Signaling Complex Mediates Dopaminergic Neurotransmission and Behavior
Beaulieu, J., Sotnikova, T. D., Marion, S., Lefkowitz, R. J., Gainetdinov, R. R., & Caron, M. G. (2005) · Cell · doi:10.1016/j.cell.2005.05.012 · Cited by 980 · see citing works
Modulation of Akt kinase activity by binding to Hsp90
Sato, S., Fujita, N., & Tsuruo, T. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.170276797 · Cited by 967 · see citing works
Gao, T., Furnari, F., & Newton, A. C. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.03.008 · Cited by 906 · see citing works
Advances in protein kinase B signalling: AKTion on multiple fronts
Brazil, D. P., Yang, Z., & Hemmings, B. A. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2004.03.006 · Cited by 830 · see citing works
Erk Associates with and Primes GSK-3β for Its Inactivation Resulting in Upregulation of β-Catenin
Ding, Q., Xia, W., Liu, J.-C., Yang, J.-Y., Lee, D.-F., Xia, J., Bartholomeusz, G., Li, Y., Pan, Y., Li, Z., et al. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.06.009 · Cited by 597 · see citing works
Andjelkovic, M., Jakubowicz, T., Cron, P., Ming, X., Han, J. W., & Hemmings, B. (1996) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.93.12.5699 · Cited by 525 · see citing works
Crystal structure of an activated Akt/Protein Kinase B ternary complex with GSK3-peptide and AMP-PNP
Yang, J., Cron, P. D., Good, V. M., Thompson, V., Hemmings, B. A., & Barford, D. (2002) · Nature Structural Biology · doi:10.1038/nsb870 · Cited by 505 · see citing works
Regulation of β-Catenin Signaling by the B56 Subunit of Protein Phosphatase 2A
Seeling, J. M., Miller, J. R., Gil, R., Moon, R. T., White, R. L., & Virshup, D. M. (1999) · Science · doi:10.1126/science.283.5410.2089 · Cited by 421 · see citing works
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 · see citing works
IEX -1L, an Apoptosis Inhibitor Involved in NF-κB-Mediated Cell Survival
Wu, M. X., Ao, Z., Prasad, K. V. S., Wu, R., & Schlossman, S. F. (1998) · Science · doi:10.1126/science.281.5379.998 · Cited by 414 · see citing works
Identification of a tumour suppressor network opposing nuclear Akt function
Trotman, L. C., Alimonti, A., Scaglioni, P. P., Koutcher, J. A., Cordon‐Cardo, C., & Pandolfi, P. P. (2006) · Nature · doi:10.1038/nature04809 · Cited by 388 · see citing works
Tcl1 enhances Akt kinase activity and mediates its nuclear translocation
Pekarsky, Y., Koval, A. P., Hallas, C., Bichi, R., Tresini, M., Malstrom, S. E., Russo, G., Tsichlis, P. N., & Croce, C. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3028 · Cited by 342 · see citing works
Protein phosphatase 2A: the Trojan Horse of cellular signaling
Sontag, E. (2001) · Cellular Signalling · doi:10.1016/s0898-6568(00)00123-6 · Cited by 328 · see citing works
Identification of specific PP2A complexes involved in human cell transformation
Chen, W., Possemato, R., Campbell, K. T., Plattner, C. A., Pallas, D. C., & Hahn, W. C. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00026-1 · Cited by 325 · see citing works
Li, L., Ren, C. H., Tahir, S. A., Ren, C., & Thompson, T. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9389-9404.2003 · Cited by 291 · see citing works
Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase
Zhao, J. J., Gjoerup, O. V., Subramanian, R. R., Cheng, Y., Chen, W., Roberts, T. M., & Hahn, W. C. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00088-6 · Cited by 280 · see citing works
Arnold, H. K., & Sears, R. C. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.7.2832-2844.2006 · Cited by 251 · see citing works
Ugi, S., Imamura, T., Maegawa, H., Egawa, K., Yoshizaki, T., Shi, K., Obata, T., Ebina, Y., Kashiwagi, A., & Olefsky, J. M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.19.8778-8789.2004 · Cited by 241 · see citing works
Brami‐Cherrier, K., Valjent, E., García, M., Pagès, C., Hipskind, R. A., & Caboche, J. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-20-08911.2002 · Cited by 230 · see citing works
Letourneux, C., Rocher, G., & Porteu, F. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7600980 · Cited by 224 · see citing works
Self-citationRuvolo, P. P., Clark, W., Mumby, M. C., Gao, F., & May, W. S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201830200 · Cited by 153 · see citing works
Resjö, S., Göransson, O., Härndahl, L., Zołnierowicz, S., Manganiello, V. C., & Degerman, E. (2002) · Cellular Signalling · doi:10.1016/s0898-6568(01)00238-8 · Cited by 142 · see citing works
Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase
Wang, Q., Zhou, Y., Wang, X., & Evers, B. M. (2005) · Oncogene · doi:10.1038/sj.onc.1209004 · Cited by 141 · see citing works
Adams, D. G., Coffee, R. L., Zhang, H., Pelech, S., Strack, S., & Wadzinski, B. E. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502464200 · Cited by 133 · see citing works
Regulation of Apoptosis by the Ft1 Protein, a New Modulator of Protein Kinase B/Akt
Remy, I., & Michnick, S. W. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.4.1493-1504.2004 · Cited by 121 · see citing works
Roles of the stress-induced gene IEX-1 in regulation of cell death and oncogenesis
Wu, M. X. (2003) · APOPTOSIS · doi:10.1023/a:1021688600370 · Cited by 120 · see citing works
IEX‐1: a new ERK substrate involved in both ERK survival activity and ERK activation
Garcia, J., Ye, Y., Arranz, V., Letourneux, C., Pézeron, G., & Porteu, F. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf488 · Cited by 108 · see citing works
Self-citationArlt, A., Grobe, O., Sieke, A., Kruse, M., Fölsch, U. R., Schmidt, W. E., & Schäfer, H. (2001) · Oncogene · doi:10.1038/sj.onc.1204061 · Cited by 88 · see citing works
Porteu, F., Rouyez, M.-C., Petit, L., et al. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.2473 · Cited by 88 · see citing works
Self-citationPR72, a novel regulator of Wnt signaling required for Naked cuticle functionPreprint
Creyghton, M. P., Roël, G., Eichhorn, P. J. A., Hijmans, E. M., Maurer, I., Destrée, O., & Bernards, R. (2005) · Genes & Development · doi:10.1101/gad.328905 · Cited by 74 · see citing works
Schulze, A., Nicke, B., Warne, P. H., Tomlinson, S. R., & Downward, J. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-11-0807 · Cited by 72 · see citing works
IEX-1, an immediate early gene, increases the rate of apoptosis in keratinocytes
Schilling, D., Pittelkow, M. R., & Kumar, R. (2001) · Oncogene · doi:10.1038/sj.onc.1204965 · Cited by 68 · see citing works
JNK-interacting Protein 1 Promotes Akt1 Activation
Kim, A. H., Sasaki, T., & Chao, M. V. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305349200 · Cited by 60 · see citing works
Distinct Domains for Anti- and Pro-apoptotic Activities of IEX-1
Li, S., Guo, J., Santos‐Berríos, C., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600054200 · Cited by 55 · see citing works
E7 Abolishes Raf-Induced Arrest via Mislocalization of p21Cip1
Westbrook, T. F., Nguyen, D. X., Thrash, B. R., & McCance, D. J. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.20.7041-7052.2002 · Cited by 53 · see citing works
Charles, C. H., Yoon, J. K., Simske, J. S., et al. (1993) · PubMed · Cited by 52 · see citing works
Domachowske, J. B., Bonville, C. A., Mortelliti, A. J., Colella, C. B., Kim, U., & Rosenberg, H. F. (2000) · The Journal of Infectious Diseases · doi:10.1086/315319 · Cited by 47 · see citing works
Thrombopoietin regulates IEX-1 gene expression through ERK-induced AML1 phosphorylation
Hamelin, V., Letourneux, C., Roméo, P., Porteu, F., & Gaudry, M. (2005) · Blood · doi:10.1182/blood-2005-07-2953 · Cited by 46 · see citing works
Self-citationB56 Regulatory Subunit of Protein Phosphatase 2A Mediates Valproic Acid-Induced p300 Degradation
Chen, J., St‐Germain, J. R., & Li, Q. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.2.525-532.2005 · Cited by 41 · see citing works
Yamada, T., Katagiri, H., Asano, T., Inukai, K., Tsuru, M., Kodama, T., Kikuchi, M., & Oka, Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m005685200 · Cited by 37 · see citing works
Analysis of the ERK1,2 transcriptome in mammary epithelial cells
Grill, C. J., Gheyas, F., Dayananth, P., Jin, W., Ding, W., Ping, Q. I. U., Wang, L., Doll, R. J., & English, J. M. (2004) · Biochemical Journal · doi:10.1042/bj20031688 · Cited by 30 · see citing works
Development of T-cell lymphomas in Eμ-IEX-1 mice
Zhang, Y., Finegold, M. J., Porteu, F., Kanteti, P. V. S., & Wu, M. X. (2003) · Oncogene · doi:10.1038/sj.onc.1206707 · Cited by 29 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Kuo, Y.-C., Huang, K.-Y., Yang, C.-H., Yang, Y.-S., Lee, W.-Y., & Chiang, C.-W. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709585200 · Cited by 367 · see citing works
Ruvolo, P. P. (2016) · BBA Clinical · doi:10.1016/j.bbacli.2016.08.002 · Cited by 143 · see citing works
Haesen, D., Abbasi Asbagh, L., Derua, R., Hubert, A., Schrauwen, S., Hoorne, Y., Amant, F., Waelkens, E., Sablina, A., & Janssens, V. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-3342 · Cited by 124 · see citing works
Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56
Wang, J., Okkeri, J., Pavic, K., Wang, Z., Kauko, O., Halonen, T., Sarek, G., Ojala, P. M., Rao, Z., Xu, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201642788 · Cited by 95 · see citing works
Clk2 and B56β mediate insulin-regulated assembly of the PP2A phosphatase holoenzyme complex on Akt
Rodgers, J. T., Vogel, R. O., & Puigserver, P. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.007 · Cited by 99 · see citing works
Meeusen, B., & Janssens, V. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.10.002 · Cited by 96 · see citing works
Loveday, C., Tatton-Brown, K., Clarke, M., Westwood, I., Renwick, A., Ramsay, E., Nemeth, A., Campbell, J., Joss, S., Gardner, M., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv182 · Cited by 87 · see citing works
Jackson, J. B., & Pallas, D. C. (2012) · Neoplasia · doi:10.1593/neo.12768 · Cited by 60 · see citing works
Andrade, E. C., Musante, V., Horiuchi, A., Matsuzaki, H., Brody, A. H., Wu, T., Greengard, P., Taylor, J. R., & Nairn, A. C. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.4559-15.2017 · Cited by 41 · see citing works
MacKay, K. B., Tu, Y., Young, S. G., & Clarke, S. G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065967 · Cited by 14 · see citing works
Molecular mechanism of PP2A/B55α phosphatase inhibition by IER5
Cao, R., Jones, D. T. D., Pan, L., Yang, A., Wang, S., Padi, S. K. R., Rawson, S., Aster, J. C., & Blacklow, S. C. (2025) · Cell Chemical Biology · doi:10.1016/j.chembiol.2025.03.004 · Cited by 7 · see citing works
- Authors
- Rocher, G., Letourneux, C., Lenormand, P., & Porteu, F.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Porteu, Françoise
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 282
- Issue
- 8
- Pages
- 5468-5477
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2078015812
- Cited by
- 87
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 5 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 5 · 2014: 2 · 2013: 8 · 2012: 4
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- IEX-1, protein phosphatase 2A, Akt, ERK signaling, Akt dephosphorylation, PP2A holoenzyme, Akt activation, early response genes, growth factor signaling
- MeSH terms
- Animals, Cricetulus, Enzyme Activation, Cricetinae, Mutation, Phosphoprotein Phosphatases, Phosphorylation, Gene Expression, CHO Cells, Immediate-Early Proteins, MAP Kinase Signaling System, Protein Subunits, RNA Interference, Intercellular Signaling Peptides and Proteins, NIH 3T3 Cells, Protein Modification, Translational, Multiprotein Complexes, Extracellular Signal-Regulated MAP Kinases, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review