Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes

Adams, Deanna G.; Coffee, R. Lane; Zhang, Hong; Pelech, Steven; Strack, Stefan; Wadzinski, Brian E.

doi:10.1074/jbc.m502464200

Cited by 135Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingMelanoma and MAPK Pathways

Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes

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Adams, Deanna G., Coffee, R. Lane, Zhang, Hong, Pelech, Steven, Strack, Stefan, Wadzinski, Brian E.·2005·Journal of Biological Chemistry

DOI 10.1074/jbc.m502464200

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Abstract

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-function experiments in serum-starved HEK cells supported a role for PP2A/B55 trimers in MEK1/2 and ERK1/2 activation through RAF1.
“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
PP2A/B55α and B55δ dephosphorylate RAF1 at Ser259.
“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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Identification of Radiation-Induced miRNA Biomarkers Using the CGL1 Cell Model System
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Isolation and Characterization of PP2A Holoenzymes Containing FLAG-Tagged B Subunits
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Distinct Protein Phosphatase 2A Heterotrimers Modulate Growth Factor Signaling to Extracellular Signal-regulated Kinases and Akt
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Raf-1-associated Protein Phosphatase 2A as a Positive Regulator of Kinase Activation
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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.
ORCID: Coffee, R. Lane
Pelech, Steven
Strack, Stefan
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)
DOI: 10.1074/jbc.m502464200
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5419 d)
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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Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes

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