Gene interactions and pathways from curated databases and text-mining
Curr Biol 2003, PMID: 12932319

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

Ory, St├ęphane; Zhou, Ming; Conrads, Thomas P; Veenstra, Timothy D; Morrison, Deborah K

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.

Diseases/Pathways annotated by Medline MESH: MAP Kinase Signaling System
Document information provided by NCBI PubMed

Text Mining Data

ERK → PP2A: " 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 "

Manually curated Databases

  • NCI Pathway Database PDGFR-beta signaling pathway: BRAF/14-3-3 (dimer) complex (BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: BRAF/14-3-3 (dimer) complex (BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → KSR (KSR1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: BRAF/14-3-3 (dimer) complex (BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: BRAF/14-3-3 (dimer) complex (BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → BRAF/14-3-3 complex (BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) → BRAF/14-3-3 complex (BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: KSR (KSR1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: KSR (KSR1) → BRAF/14-3-3 complex (BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → BRAF/14-3-3 complex (BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: KSR/14-3-3 (dimer)/MEK1-2-active complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB-MAP2K1_MAP2K2) → KSR/14-3-3 /MEK1-2 complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB-MAP2K1_MAP2K2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: KSR/14-3-3 /MEK1-2 complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB-MAP2K1_MAP2K2) → RAF1/BRAF/14-3-3/14-3-3 complex (RAF1-BRAF) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: Erk1-2 (MAPK3/MAPK1) → MEK1-2-active (MAP2K1/MAP2K2) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: Erk1-2 (MAPK3/MAPK1) → Erk1-2-active (MAPK3/MAPK1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: MEK1-2-active (MAP2K1/MAP2K2) → Erk1-2-active (MAPK3/MAPK1) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: Erk1-2 (MAPK3/MAPK1) → KSR/14-3-3 (dimer)/MEK1-2-active complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB-MAP2K1_MAP2K2) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: Erk1-2 (MAPK3/MAPK1) → Erk1-2-active (MAPK3/MAPK1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: KSR/14-3-3 (dimer)/MEK1-2-active complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB-MAP2K1_MAP2K2) → Erk1-2-active (MAPK3/MAPK1) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database ErbB1 downstream signaling: PPP2R1A/PPP2CA/PPP2R2A complex (PPP2R1A-PPP2CA-PPP2R2A) → KSR/14-3-3 complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, activates)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: PPP2R1A/PPP2CA/PPP2R2A complex (PPP2R1A-PPP2CA-PPP2R2A) → 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) (modification, activates)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: PPP2R1A/PPP2CA/PPP2R2A complex (PPP2R1A-PPP2CA-PPP2R2A) → KSR (KSR1) (modification, activates)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: KSR/14-3-3 complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: KSR/14-3-3 complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → KSR (KSR1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) → KSR (KSR1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database PDGFR-beta signaling pathway: RAF1/14-3-3 complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → RAF1/14-3-3 (dimer) complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: RAF1/14-3-3 complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: PP2A complex (PPP2R1A-PPP2R2B-PPP2CA) → RAF1/14-3-3 (dimer) complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: PP2A complex (PPP2R1A-PPP2R2B-PPP2CA) → 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: PP2A complex (PPP2R1A-PPP2R2B-PPP2CA) → KSR (KSR1) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: PP2A complex (PPP2R1A-PPP2R2B-PPP2CA) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: RAF1/14-3-3 (dimer) complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: RAF1/14-3-3 (dimer) complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → KSR (KSR1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: RAF1/14-3-3 (dimer) complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: KSR (KSR1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: PIN1 (PIN1) → PP2A complex (PPP2R1A-PPP2R2B-PPP2CA) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: KSR/14-3-3 /MEK1-2 complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB-MAP2K1_MAP2K2) → 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database PDGFR-beta signaling pathway: KSR/14-3-3 /MEK1-2 complex (KSR1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB-MAP2K1_MAP2K2) → KSR/14-3-3 (dimer)/MEK1-2 complex (KSR1-MAP2K1_MAP2K2) (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database PDGFR-beta signaling pathway: PP2A complex (PPP2R1A-PPP2R2B-PPP2CA) → 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) (modification, activates)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database PDGFR-beta signaling pathway: PP2A complex (PPP2R1A-PPP2R2B-PPP2CA) → KSR/14-3-3 (dimer)/MEK1-2 complex (KSR1-MAP2K1_MAP2K2) (modification, activates)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database PDGFR-beta signaling pathway: 14-3-3 family (YWHAH/YWHAZ/YWHAQ/SFN/YWHAE/YWHAG/YWHAB) → KSR/14-3-3 (dimer)/MEK1-2 complex (KSR1-MAP2K1_MAP2K2) (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database ErbB1 downstream signaling: PPP2R1A/PPP2CA/PPP2R2A complex (PPP2R1A-PPP2CA-PPP2R2A) → PPP2R1A/PPP2CA complex (PPP2R1A-PPP2CA) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: PPP2R1A/PPP2CA/PPP2R2A complex (PPP2R1A-PPP2CA-PPP2R2A) → PPP2R2A (PPP2R2A) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: PPP2R1A/PPP2CA complex (PPP2R1A-PPP2CA) → PPP2R2A (PPP2R2A) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: PPP2R1A/PPP2CA complex (PPP2R1A-PPP2CA) → EGFR/EGFR/EGF/EGF complex (EGFR-EGF) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database ErbB1 downstream signaling: PPP2R2A (PPP2R2A) → EGFR/EGFR/EGF/EGF complex (EGFR-EGF) (modification, collaborate)
    Evidence: assay
In total, 199 gene pairs are associated to this article in curated databases