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Cited by 299Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesMelanoma and MAPK Pathways

Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites

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Ory, Stéphane, Zhou, Ming, Conrads, Thomas P, Veenstra, Timothy D, Morrison, Deborah K·2003·Current Biology
DOI 10.1016/s0960-9822(03)00535-9
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Abstract

Background Kinase Suppressor of Ras (KSR) is a conserved component of the Ras pathway that acts as a molecular scaffold to facilitate signal transmission through the MAPK cascade. Although recruitment of KSR1 from the cytosol to the plasma membrane is required for its scaffolding function, the precise mechanism(s) regulating the translocation of KSR1 have not been fully elucidated.Results Using mass spectrometry to analyze the KSR1-scaffolding complex, we identify the serine/threonine protein phosphatase PP2A as a KSR1-associated protein and show that PP2A is a critical regulator of KSR1 activity. We find that the enzymatic core subunits of PP2A (PR65A and catalytic C) constitutively associate with the N-terminal domain of KSR1, whereas binding of the regulatory PR55B subunit is induced by growth factor treatment. Specific inhibition of PP2A activity prevents the growth factor-induced dephosphorylation event involved in the membrane recruitment of KSR1 and blocks the activation of KSR1-associated MEK and ERK. Moreover, we find that PP2A activity is required for activation of the Raf-1 kinase and that both Raf and KSR1 must be dephosphorylated by PP2A on critical regulatory 14-3-3 binding sites for KSR1 to promote MAPK pathway activation.Conclusions These findings identify KSR1 as novel substrate of PP2A and demonstrate the inducible dephosphorylation of KSR1 in response to Ras pathway activation. Further, these results elucidate a common regulatory mechanism for KSR1 and Raf-1 whereby their localization and activity are modulated by the PP2A-mediated dephosphorylation of critical 14-3-3 binding sites.

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  • PP2A/B55α holoenzyme subunits were found in immunopurified RAF1, and PDGF stimulated B55α recruitment to RAF1-PP2A/AC.

    “The three subunits of the PP2A/B55α holoenzyme were detected in immunopurified RAF1 by mass spectrometry and B55α recruitment to the RAF1-PP2A/AC complex was stimulated by PDGF, which stimulates RAF1-Ser259 dephosphorylation (Ory et al., 2003).”

    From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Ory et al., 2003

  • PDGF treatment causes PP2A/B55 to dephosphorylate KSR1 at Ser392, releasing it from 14-3-3 and allowing membrane translocation that helps activate MAPK.

    “Upon PDGF treatment, PP2A/B55 dephosphorylates KSR1 on Ser392, which releases it from 14-3-3 and allows it to translocate to the cell membrane to facilitate MAPK pathway activation (Ory et al., 2003).”

    From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Ory et al., 2003

  • KSR1 is a PP2A dephosphorylation target, and PP2A core dimer and B55α were identified in immunopurified KSR1.

    “Kinase Suppressor of Ras 1 (KSR1), the molecular scaffold that assembles the MAPK pathway, is also a dephosphorylation target of PP2A, as mass spectrometry analysis identified the PP2A core dimer and B55α in immunopurified KSR1.”

    From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Ory et al., 2003

  • 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 Ory et al., 2003

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Authors
Ory, S., Zhou, M., Conrads, T. P., Veenstra, T. D., & Morrison, D. K.
Affiliations
  • Frederick National Laboratory for Cancer Research (US)
  • Science Applications International Corporation (United States) (US)
Corresponding author
Morrison, Deborah K
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2003-08
Volume
13
Issue
16
Pages
1356-1364
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/s0960-9822(03)00535-9
OpenAlex
W2166077873
Cited by
296
References
41
Citations by year
2026: 1 · 2025: 7 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 14 · 2019: 12 · 2018: 10 · 2017: 10 · 2016: 11 · 2015: 9 · 2014: 13 · 2013: 16 · 2012: 12
FWCI
7.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
  • DigitalCommons-Cedarville (Cedarville University) (submittedVersion)
  • HAL (submittedVersion)
Funders
U.S. Public Health Service (N01C012400)
Topics
  • 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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
protein phosphatase 2A, KSR1, Raf-1, Ras signaling, MAPK signaling, dephosphorylation, membrane recruitment, MEK activation, ERK activation, growth factor signaling, scaffold proteins
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Enzyme Activation, Models, Biological, Molecular Sequence Data, Peptide Fragments, Phosphoprotein Phosphatases, Phosphorylation, Protein Kinases, Recombinant Proteins, Substrate Specificity, Tyrosine 3-Monooxygenase, Signal Transduction, 3T3 Cells, ras Proteins, COS Cells, Proto-Oncogene Proteins c-raf, MAP Kinase Signaling System, 14-3-3 Proteins, Mice, Protein Phosphatase 2, In Vitro Techniques

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