We have a suspicion that you are an automated web bot software, not a real user. To keep our site fast for other users, we have slowed down this page. The slowdown will gradually disappear. If you think this is a mistake, please contact us at genome-www@soe.ucsc.edu. Also note that all data for hgGeneGraph can be obtained through our public MySQL server and all our software source code is available and can be installed locally onto your own computer. If you are unsure how to use these resources, do not hesitate to contact us.
UCSC Genome Browser Gene Interaction Graph
Gene interactions and pathways from curated databases and text-mining
Cell Signal 2009, PMID: 19595761

The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch.

Dhillon, Amardeep S; Yip, Yan Yan; Grindlay, G Joan; Pakay, Julian L; Dangers, Marc; Hillmann, Meike; Clark, William; Pitt, Andrew; Mischak, Harald; Kolch, Walter

The Raf-1 protein kinase is a major activator of the ERK MAPK pathway, which links signaling by a variety of cell surface receptors to the regulation of cell proliferation, survival, differentiation and migration. Signaling by Raf-1 is regulated by a complex and poorly understood interplay between phosphorylation events and protein-protein interactions. One important mode of Raf-1 regulation involves the phosphorylation-dependent binding of 14-3-3 proteins. Here, we have examined the mechanism whereby the C-terminal 14-3-3 binding site of Raf-1, S621, controls the activation of MEK-ERK signaling. We show that phosphorylation of S621 turns over rapidly and is enriched in the activated pool of endogenous Raf-1. The phosphorylation on this site can be mediated by Raf-1 itself but also by other kinase(s). Mutations that prevent the binding of 14-3-3 proteins to S621 render Raf-1 inactive by specifically disrupting its capacity to bind to ATP, and not by gross conformational alteration as indicated by intact MEK binding. Phosphorylation of S621 correlates with the inhibition of Raf-1 catalytic activity in vitro, but 14-3-3 proteins can completely reverse this inhibition. Our findings suggest that 14-3-3 proteins function as critical cofactors in Raf-1 activation, which induce and maintain the protein in a state that is competent for both ATP binding and MEK phosphorylation.

Document information provided by NCBI PubMed

Text Mining Data

Dashed line = No text mining data

Manually curated Databases

  • IRef Intact Interaction: RAF1 — YWHAB (association, biochemical)
  • NCI Pathway Database ErbB1 downstream signaling: YWHAZ/YWHAZ complex (YWHAZ) → KSR (KSR1) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database ErbB1 downstream signaling: YWHAZ/YWHAZ complex (YWHAZ) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database ErbB1 downstream signaling: KSR (KSR1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • 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
In total, 110 gene pairs are associated to this article in curated databases