Gene interactions and pathways from curated databases and text-mining
Mol Cell 2005, PMID: 15664191

Regulation of Raf-1 by direct feedback phosphorylation.

Dougherty, Michele K; Müller, Jürgen; Ritt, Daniel A; Zhou, Ming; Zhou, Xiao Zhen; Copeland, Terry D; Conrads, Thomas P; Veenstra, Timothy D; Lu, Kun Ping; Morrison, Deborah K

The Raf-1 kinase is an important signaling molecule, functioning in the Ras pathway to transmit mitogenic, differentiative, and oncogenic signals to the downstream kinases MEK and ERK. Because of its integral role in cell signaling, Raf-1 activity must be precisely controlled. Previous studies have shown that phosphorylation is required for Raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of Raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli. The hyperphosphorylated/desensitized Raf-1 is subsequently dephosphorylated and returned to a signaling-competent state through interactions with the protein phosphatase PP2A and the prolyl isomerase Pin1. These findings elucidate a critical Raf-1 regulatory mechanism that contributes to the sensitive, temporal modulation of Ras signaling.

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Text Mining Data

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Manually curated Databases

  • IRef Bind Interaction: RAF1 — PIN1
  • IRef Bind Interaction: RAF1 — HRAS
  • IRef Bind Interaction: Complex of 16 proteins
  • IRef Bind_translation Interaction: RAF1 — MAPK1 (experimental interaction detection)
  • IRef Bind_translation Interaction: RAF1 — PIN1 (coimmunoprecipitation)
  • IRef Bind_translation Interaction: RAF1 — PIN1 (affinity chromatography technology)
  • IRef Bind_translation Interaction: RAF1 — HRAS (affinity chromatography technology)
  • IRef Biogrid Interaction: RAF1 — MAPK1 (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: RAF1 — PIN1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RAF1 — HRAS (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RAF1 — YWHAZ (physical association, affinity chromatography technology)
  • MIPS CORUM RAF1-PPP2-PIN1 complex: RAF1-PPP2-PIN1 complex complex (PIN1-PPP2CB-PPP2R1A-PPP2R2A-RAF1)
  • IRef Hprd Interaction: RAF1 — MAPK1 (in vivo)
  • IRef Hprd Interaction: RAF1 — MAPK1 (in vitro)
  • IRef Hprd Interaction: RAF1 — PIN1 (in vitro)
  • IRef Hprd Interaction: RAF1 — PIN1 (in vivo)
  • NCI Pathway Database PDGFR-beta signaling pathway: Erk1-2-active (MAPK3/MAPK1) → RAF1/14-3-3 complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: Erk1-2-active (MAPK3/MAPK1) → RAF1/BRAF/14-3-3/14-3-3 complex (RAF1-BRAF-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database PDGFR-beta signaling pathway: Erk1-2-active (MAPK3/MAPK1) → 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: RAF1/14-3-3 complex (RAF1-YWHAH_YWHAZ_YWHAQ_SFN_YWHAE_YWHAG_YWHAB) → RAF1/BRAF/14-3-3/14-3-3 complex (RAF1-BRAF-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) → 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: RAF1/BRAF/14-3-3/14-3-3 complex (RAF1-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: PIN1 (PIN1) → PP2A complex (PPP2R1A-PPP2R2B-PPP2CA) (modification, activates)
    Evidence: assay, physical interaction
In total, 79 gene pairs are associated to this article in curated databases