Cited by 372PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingSignaling Pathways in Disease

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Regulation of Phosphorylation of Thr-308 of Akt, Cell Proliferation, and Survival by the B55α Regulatory Subunit Targeting of the Protein Phosphatase 2A Holoenzyme to Akt

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Kuo, Yi-Chun, Huang, Kai-Yun, Yang, Chung-Hsiang, Yang, Yu-San, Lee, Wen-Yu, Chiang, Chi-Wu·2008·Journal of Biological Chemistry

DOI 10.1074/jbc.m709585200

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Abstract

Akt is a protein serine/threonine kinase that is involved in the regulation of diverse cellular processes. Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells. Akt was shown to associate with ectopically expressed B55alpha subunit in NIH3T3 cells. The direct interaction between B55alpha subunit and Akt was confirmed using in vitro pulldown analyses. Intriguingly, we found that overexpression of B55alpha subunit significantly impaired phosphorylation at Thr-308, but to a lesser extent at Ser-473 of Akt in both FL5.12 and NIH3T3 cells. Concomitantly, phosphorylation of a subset of Akt substrates, including FoxO3a, was substantially decreased by B55alpha overexpression in these cells. Silencing of B55alpha expression markedly increased phosphorylation at Thr-308 but not at Ser-473 in both FL5.12 cells and NIH3T3 cells. Consistently, PP2A AB55alphaC holoenzymes preferentially dephosphorylated phospho-Thr-308 rather than phospho-Ser-473 in in vitro dephosphorylation assays. Furthermore, B55alpha overexpression retarded proliferation of NIH3T3 cells, and knockdown of B55alpha expression increased survival of FL5.12 cells upon interleukin-3 deprivation. Together, our data demonstrate that B55alpha-dependent targeting of the PP2A holoenzyme to Akt selectively regulates Akt phosphorylation at Thr-308 to regulate cell proliferation and survival.

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Authors: Kuo, Y.-C., Huang, K.-Y., Yang, C.-H., Yang, Y.-S., Lee, W.-Y., & Chiang, C.-W.
Affiliations: National Cheng Kung University (TW)
Corresponding author: Chiang, Chi-Wu
ORCID: Yang, Chung-Hsiang
Yang, Yu-San
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2008-01
Volume: 283
Issue: 4
Pages: 1882-1892
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m709585200
OpenAlex: W2045852899
Cited by: 367
References: 72
Citations by year: 2026: 12 · 2025: 18 · 2024: 14 · 2023: 15 · 2022: 23 · 2021: 22 · 2020: 27 · 2019: 20 · 2018: 25 · 2017: 30 · 2016: 20 · 2015: 32 · 2014: 26 · 2013: 18 · 2012: 17
FWCI: 4.24
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4659 d)
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 › Signaling Pathways in Disease
Keywords: Akt, protein phosphatase 2A, PP2A holoenzyme, Akt dephosphorylation, FOXO3, cell proliferation, cell survival, NIH3T3 cells
MeSH terms: Animals, Cell Survival, Humans, Interleukin-3, Phosphorylation, Holoenzymes, Gene Silencing, NIH 3T3 Cells, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Protein Phosphatase 2

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Regulation of Phosphorylation of Thr-308 of Akt, Cell Proliferation, and Survival by the B55α Regulatory Subunit Targeting of the Protein Phosphatase 2A Holoenzyme to Akt

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