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Positive Regulation of Raf1-MEK1/2-ERK1/2 Signaling by Protein Serine/Threonine Phosphatase 2A Holoenzymes
Open accessAbstract
Protein serine/threonine phosphatase 2A (PP2A) regulates a wide variety of cellular signal transduction pathways. The predominant form of PP2A in cells is a heterotrimeric holoenzyme consisting of a scaffolding (A) subunit, a regulatory (B) subunit, and a catalytic (C) subunit. Although PP2A is known to regulate Raf1-MEK1/2-ERK1/2 signaling at multiple steps in this pathway, the specific PP2A holoenzymes involved remain unclear. To address this question, we established tetracycline-inducible human embryonic kidney 293 cell lines for overexpression of FLAG-tagged Balpha/delta regulatory subunits by approximately 3-fold or knock-down of Balpha by greater than 70% compared with endogenous levels. The expression of functional epitope-tagged B subunits was confirmed by the detection of A and C subunits as well as phosphatase activity in FLAG immune complexes from extracts of cells overexpressing the FLAG-Balpha/delta subunit. Western analysis of the cell extracts using phosphospecific antibodies for MEK1/2 and ERK1/2 demonstrated that activation of these kinases in response to epidermal growth factor was markedly diminished in Balpha knock-down cells but elevated in Balpha- and Bdelta-overexpressing cells as compared with control cells. In parallel with the activation of MEK1/2 and ERK1/2, the inhibitory phosphorylation site of Raf1 (Ser-259) was dephosphorylated in cells overexpressing Balpha or Bdelta. Pharmacological inhibitor studies as well as reporter assays for ERK-dependent activation of the transcription factor Elk1 revealed that the PP2A holoenzymes ABalphaC and ABdeltaC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. Together these findings indicate that PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1.
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“Loss and gain of B55α and B55δ function in serum-starved HEK cells re-stimulated with EGF confirmed the implication of PP2A/B55 trimeric holoenzymes in MEK1/2 and ERK1/2 activation via RAF1 activation (Adams et al., 2005).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Adams et al., 2005
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“In the MAPK pathway, PP2A/B family members B55α and B55δ dephosphorylate RAF1 on Ser259 (Adams et al., 2005; Ory et al., 2003), a residue that when phosphorylated inhibits RAF1 kinase by binding to 14-3-3 proteins (Abraham et al., 2000; Jaumot and Hancock, 2001).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Adams et al., 2005
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Reactive Oxygen Species-Induced Activation of the MAP Kinase Signaling Pathways
McCubrey, J. A., LaHair, M. M., & Franklin, R. A. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.1775 · Cited by 814
The Diverse Roles of Arrestin Scaffolds in G Protein–Coupled Receptor Signaling
Peterson, Y. K., & Luttrell, L. M. (2017) · Pharmacological Reviews · doi:10.1124/pr.116.013367 · Cited by 447
PP2A as a master regulator of the cell cycle
Wlodarchak, N., & Xing, Y. (2016) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2016.1143913 · Cited by 380
Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling
Luttrell, L. M., Gesty‐Palmer, D., & Sibley, D. R. (2010) · Pharmacological Reviews · doi:10.1124/pr.109.002436 · Cited by 387
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
Metadata
- Authors
- Adams, D. G., Coffee, R. L., Zhang, H., Pelech, S., Strack, S., & Wadzinski, B. E.
- Affiliations
- Vanderbilt University Medical Center (US)
- Kinexus Bioinformatics Corporation (Canada) (CA)
- University of British Columbia (CA)
- University of Iowa (US)
- Corresponding author
- Wadzinski, Brian E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 280
- Issue
- 52
- Pages
- 42644-42654
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2055476265
- Cited by
- 133
- References
- 55
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 7 · 2015: 4 · 2014: 9 · 2013: 10 · 2012: 9
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University (DK20593, CA68485)
- Vanderbilt-Ingram Cancer Center (CA68485)
- National Institutes of Health (CA68485, DK 20593)
- Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center (DK-20593)
- National Institute of Mental Health (MH19732, T32MH019732)
- National Cancer Institute (CA68485, P30CA068485)
- National Institute of General Medical Sciences (R01GM062265, GM-51366, GM62265)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 20593, T32DK007563)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- Raf-1, MEK1/2, ERK1/2, MAPK signaling, PP2A holoenzyme, epidermal growth factor, Ras
- MeSH terms
- Epitopes, Cell Line, Enzyme Activation, Enzyme Inhibitors, Humans, Luciferases, Phosphoprotein Phosphatases, Phosphorylation, Plasmids, Serine, Tetracycline, Transfection, Immunoblotting, Blotting, Western, Signal Transduction, Gene Expression Regulation, Enzymologic, Dimerization, Proto-Oncogene Proteins c-raf, Mitogen-Activated Protein Kinase 1, Reverse Transcriptase Polymerase Chain Reaction, Catalytic Domain, MAP Kinase Signaling System, RNA Interference, Immunoprecipitation, Mitogen-Activated Protein Kinase 3, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Protein Phosphatase 2
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