PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms
Open accessAbstract
Akt/protein kinase B controls cell growth, proliferation, and survival. We recently discovered a novel phosphatase PHLPP, for PH domain leucine-rich repeat protein phosphatase, which terminates Akt signaling by directly dephosphorylating and inactivating Akt. Here we describe a second family member, PHLPP2, which also inactivates Akt, inhibits cell-cycle progression, and promotes apoptosis. These phosphatases control the amplitude of Akt signaling: depletion of either isoform increases the magnitude of agonist-evoked Akt phosphorylation by almost two orders of magnitude. Although PHLPP1 and PHLPP2 both dephosphorylate the same residue (hydrophobic phosphorylation motif) on Akt, they differentially terminate Akt signaling by regulating distinct Akt isoforms. Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3alpha through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3. Our data unveil a mechanism to selectively terminate Akt-signaling pathways through the differential inactivation of specific Akt isoforms by specific PHLPP isoforms.
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With a high pLI score (0.92), PHLPP1 is a tumor suppressor in humans and mice.
“With a high pLI score (0.92), PHLPP1 is a tumor suppressor in humans and mice [30, 31].”
From Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity (2019) · cites this paper as [31]
Cites
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 · see citing works
The phosphatidylinositol 3-Kinase–AKT pathway in human cancer
Vivanco, I., & Sawyers, C. L. (2002) · Nature reviews. Cancer · doi:10.1038/nrc839 · Cited by 6,041 · see citing works
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., & Greenberg, M. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80405-5 · Cited by 5,689 · see citing works
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I., Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., et al. (1997) · Science · doi:10.1126/science.275.5308.1943 · Cited by 4,785 · see citing works
Cellular survival: a play in three Akts
Datta, S. R., Brunet, A., & Greenberg, M. E. (1999) · Genes & Development · doi:10.1101/gad.13.22.2905 · Cited by 4,216 · see citing works
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 · see citing works
Maehama, T., & Dixon, J. E. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13375 · Cited by 3,104 · see citing works
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.029 · Cited by 2,659 · see citing works
mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
O'Reilly, K. E., Rojo, F., She, Q.-B., Solit, D., Mills, G. B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2925 · Cited by 2,561 · see citing works
Cho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., Chu, Q., Crenshaw, E. B., Kaestner, K. H., Bartolomei, M. S., Shulman, G. I., & Birnbaum, M. J. (2001) · Science · doi:10.1126/science.292.5522.1728 · Cited by 1,837 · see citing works
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., et al. (2004) · Nature · doi:10.1038/nature02866 · Cited by 1,677 · see citing works
The glamour and gloom of glycogen synthase kinase-3
Jope, R. S., & Johnson, G. V. W. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.12.004 · Cited by 1,522 · see citing works
Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S. Y., Huang, Q., Qin, J., & Su, B. (2006) · Cell · doi:10.1016/j.cell.2006.08.033 · Cited by 1,407 · see citing works
Perturbations of the AKT signaling pathway in human cancer
Altomare, D. A., & Testa, J. R. (2005) · Oncogene · doi:10.1038/sj.onc.1209085 · Cited by 1,326 · see citing works
Mayo, L. D., & Donner, D. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181181198 · Cited by 1,230 · see citing works
Ten years of protein kinase B signalling: a hard Akt to follow
Brazil, D. P., & Hemmings, B. A. (2001) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(01)01958-2 · Cited by 1,177 · see citing works
Zhou, B. P., Liao, Y., Xia, W., Spohn, B., Lee, M., & Hung, M. (2001) · Nature Cell Biology · doi:10.1038/35060032 · Cited by 1,135 · see citing works
The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins
Harrington, L. S., Findlay, G. M., Gray, A., Толкачева, Т. А., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N. R., Cheng, S., Shepherd, P. R., et al. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403069 · Cited by 1,123 · see citing works
Biggs, W., Meisenhelder, J., Hunter, T. R., Cavenee, W. K., & Arden, K. C. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.13.7421 · Cited by 1,116 · see citing works
Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway
Pap, M., & Cooper, G. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.32.19929 · Cited by 1,046 · see citing works
Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F., & Birnbaum, M. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100462200 · Cited by 959 · see citing works
Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 genePreprint
Chen, W. S., Xu, P.-Z., Gottlob, K., Chen, M.-L., Sokol, K. A., Shiyanova, T., Roninson, I. B., Weng, W., Suzuki, R., Tobe, K., et al. (2001) · Genes & Development · doi:10.1101/gad.913901 · Cited by 926 · 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
Self-citationBrognard, J., Clark, A. S., Ni, Y., & Dennis, P. A. (2001) · PubMed · Cited by 885 · see citing works
Self-citationViglietto, G., Motti, M. L., Bruni, P., Melillo, R. M., D’Alessio, A., Califano, D., Vinci, F., Chiappetta, G., Tsichlis, P. N., Bellacosa, A., et al. (2002) · Nature Medicine · doi:10.1038/nm762 · Cited by 700 · see citing works
Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial–mesenchymal transition
Irie, H. Y., Pearline, R. V., Grueneberg, D. A., Hsia, M., Ravichandran, P., Kothari, N. H., Natesan, S., & Brugge, J. S. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200505087 · Cited by 582 · 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
Molecular Mechanism for the Regulation of Protein Kinase B/Akt by Hydrophobic Motif Phosphorylation
Yang, J., Cron, P. D., Thompson, V., Good, V. M., Heß, D., Hemmings, B. A., & Barford, D. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00550-6 · Cited by 418 · see citing works
Akt Blocks Breast Cancer Cell Motility and Invasion through the Transcription Factor NFAT
Yoeli-Lerner, M., Yiu, G. K., Rabinovitz, I., Erhardt, P., Jauliac, S., & Toker, A. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.10.033 · Cited by 403 · see citing works
Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways
Kwiatkowski, D. J., & Manning, B. D. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi260 · Cited by 395 · see citing works
Jiang, Z. Y., Zhou, Q. L., Coleman, K. A., Chouinard, M., Boese, Q., & Czech, M. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1332633100 · Cited by 378 · see citing works
The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB
Biondi, R. M., Kieloch, A., Currie, R. A., Deak, M., & Alessi, D. R. (2001) · The EMBO Journal · doi:10.1093/emboj/20.16.4380 · Cited by 377 · see citing works
Structural Basis for Discrimination of 3-Phosphoinositides by Pleckstrin Homology Domains
Ferguson, K. M., Kavran, J. M., Sankaran, V. G., Fournier, E., Isakoff, S. J., Skolnik, E. Y., & Lemmon, M. A. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00037-x · Cited by 333 · see citing works
New vectors for high level expression of recombinant proteins in bacteria
Hakes, D. J., & Dixon, J. E. (1992) · Analytical Biochemistry · doi:10.1016/0003-2697(92)90108-j · Cited by 247 · see citing works
Kunkel, M. T., Ni, Q., Tsien, R. Y., Zhang, J., & Newton, A. C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m411534200 · Cited by 220 · see citing works
Self-citationBornancin, F., & Parker, P. J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.6.3544 · Cited by 191 · see citing works
Pap, M., & Cooper, G. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.2.578-586.2002 · Cited by 164 · see citing works
EDWARDS, A. S., & Newton, A. C. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.18382 · Cited by 153 · see citing works
Self-citationCrystal structure of an inactive Akt2 kinase domain.
Huang, X., Begley, M., Morgenstern, K., Gu, Y., Rose, P., Zhao, H., & Zhu, X. (2003) · Structure · doi:10.1016/s0969-2126(02)00937-1 · Cited by 133 · see citing works
Shimizu, K., Okada, M., Nagai, K., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213214200 · Cited by 96 · see citing works
Growth Signaling: TSC Takes Its Place
Marygold, S. J., & Leevers, S. J. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01294-0 · Cited by 91 · see citing works
Probing the Function of Conserved Residues in the Serine/Threonine Phosphatase PP2Cα
Jackson, M. D., Fjeld, C. C., & Denu, J. M. (2003) · Biochemistry · doi:10.1021/bi034074+ · Cited by 71 · see citing works
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Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115 · see citing works
Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases
Beurel, E., Grieco, S. F., & Jope, R. S. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.11.016 · Cited by 1,768 · see citing works
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Shi, Y. (2009) · Cell · doi:10.1016/j.cell.2009.10.006 · Cited by 1,488 · see citing works
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Pei, H., Li, L., Fridley, B. L., Jenkins, G. D., Kalari, K. R., Lingle, W., Petersen, G., Lou, Z., & Wang, L. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.07.016 · Cited by 709 · see citing works
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“92), PHLPP1 is a tumor suppressor in humans and mice [30, 31].”
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- Authors
- Brognard, J., Sierecki, E., Gao, T., & Newton, A. C.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Newton, Alexandra C.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 25
- Issue
- 6
- Pages
- 917-931
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1984879511
- Cited by
- 591
- References
- 42
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 15 · 2023: 18 · 2022: 34 · 2021: 35 · 2020: 25 · 2019: 30 · 2018: 30 · 2017: 30 · 2016: 28 · 2015: 45 · 2014: 38 · 2013: 40 · 2012: 38
- FWCI
- 15.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Funders
- U.S. Department of Defense
- National Institutes of Health
- University of California, San Diego
- National Cancer Institute (2P30 CA 23100-18, K01CA10209, P30CA023100)
- National Institute of General Medical Sciences (R01GM067946, 5 T32 GM07752-26, T32GM007752, GM067946)
- U.S. Army Medical Research Acquisition Activity
- 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 Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- PHLPP, PHLPP2, Akt signaling, Akt isoforms, Akt dephosphorylation, AKT2, AKT3, MDM2, GSK3α, p27, cell cycle progression, apoptosis
- MeSH terms
- Amino Acid Sequence, Cell Division, Cell Line, Cloning, Molecular, Humans, Isoenzymes, Molecular Sequence Data, Nuclear Proteins, Phosphoprotein Phosphatases, Recombinant Proteins, Transfection, Signal Transduction, Sequence Alignment, Apoptosis, Sequence Homology, Amino Acid, Proto-Oncogene Proteins c-akt
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