A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity

@article{Tzivion1998AD1,
  title={A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity},
  author={Guri Tzivion and Zhijun Luo and Joseph Avruch},
  journal={Nature},
  year={1998},
  volume={394},
  pages={88-92}
}
cRaf-1 is a mitogen-activated protein kinase that is the main effector recruited by GTP-bound Ras in order to activate the MAP kinase pathway. Inactive Raf is found in the cytosol in a complex with Hsp90, Hsp50 (Cdc37), and the 14-3-3 proteins. GTP-bound Ras binds Raf and is necessary but not sufficient for the stable activation of Raf that occurs in response to serum, epidermal growth factor, platelet-derived growth factor or insulin. These agents cause a two- to threefold increase in overall… 
The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch.
Regulation of the Raf-1 kinase domain by phosphorylation and 14-3-3 association.
TLDR
The results support a model of Raf regulation in which the activity of the Raf-1 catalytic domain is directly upregulated by phosphorylation, following relief of inhibition by the N-terminal regulatory domain upon Ras-GTP binding.
Raf-1-associated Protein Phosphatase 2A as a Positive Regulator of Kinase Activation*
TLDR
PP2A is identified as a positive regulator of Raf-1 activation and the first indication that PP2A may support the activation of an associated kinase is given.
Regulation of RAF Activity by 14-3-3 Proteins
TLDR
It is found that B-RAF associates in vivo with 14-3-3 at much higher diversity than A- and C- RAF, and that A-, B-, and C -RAF activity is differentially regulated by its C-terminal and internal 14- 3-3 binding domain.
Assay of Raf-1 activity.
Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions
TLDR
It is shown that PP1 and PP2A serine-threonine phosphatases also have a positive role in Ras dependent Raf-1 activation, and observations suggest that dephosphorylation of S259 is a critical early step in Rasdependent Raf- 1 activation which facilitates 14-3-3 displacement.
Impaired Binding of 14-3-3 to C-RAF in Noonan Syndrome Suggests New Approaches in Diseases with Increased Ras Signaling
TLDR
Modulating the C-RAFSer259/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAf-MAPK pathway.
Interactions of c-Raf-1 with phosphatidylserine and 14-3-3
TLDR
It is shown here that the Raf-1 zinc finger is not absolutely required for 14-3-3 binding but is required to stabilize the interaction between Raf- 1 and 14-2-3, and that removal of 14- 3-3 from Raf-2 has markedly different effects depending on experimental conditions.
Nuclear Localization of Protein Kinase U-α Is Regulated by 14-3-3*
TLDR
The results suggest that the subcellular localization of PKUα is regulated, at least in part, by its association with 14-3-3, and the coding sequence of the human form (protein kinase Uα, PKU α) of this protein kinase was found in GenBankTMon on the basis of sequence homology.
Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization
TLDR
The data suggest that most oncogenic BRAF mutations alter interactions with ATP and counteract the negative effects of ATP binding by lowering the threshold for RAF dimerization and pathway activation, and provides new avenues for improved RAF-inhibitor discovery.
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References

SHOWING 1-10 OF 60 REFERENCES
Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation.
TLDR
A role for 14-3-3 proteins in Raf-mediated signal transduction is suggested, which may participate in or be required for the regulation of Raf function.
Activated Ras displaces 14-3-3 protein from the amino terminus of c-Raf-1.
TLDR
Bivalent binding of 14-3-3 zeta to the amino terminus as well as to the carboxy terminus of c-Raf-1 is indicated in unstimulated cells.
Oligomerization activates c-Raf-1 through a Ras-dependent mechanism
TLDR
Oligomerization of Raf per se promotes Raf activation through a Ras-dependent mechanism as with EGF, activation of FKBP-Raf by FK1012A is entirely Ras-GTP dependent.
Activation of Raf-1 by 14-3-3 proteins
TLDR
Using the yeast two-hybrid system, two structurally related proteins are identified that interact with the amino-terminal region of Raf-1 and are members of the 14-3-3 family of proteins.
Stimulatory effects of yeast and mammalian 14-3-3 proteins on the Raf protein kinase.
TLDR
Bacterially synthesized mammalian 14-3-3 protein stimulated the activity of Raf prepared from yeast cells expressing c-Raf-1, and may participate in or be required for activation of Raf.
14-3-3 ζ Negatively Regulates Raf-1 Activity by Interactions with the Raf-1 Cysteine-rich Domain*
TLDR
It is demonstrated that 14-3-3 ζ binds directly to the isolated Raf-CRD and may serve in negative regulation of Raf-1 function by facilitating dissociation of 14- 3-3 from the NH2 terminus of Raf -1 to promote subsequent events necessary for full activation of Rafael-1.
Reversal of Raf-1 activation by purified and membrane-associated protein phosphatases.
TLDR
The results suggest the existence of protein phosphatases in the cell membrane that are regulated by GTP and are responsible for Raf-1 inactivation.
Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization
TLDR
It is found that dimerization is by itself sufficient, in the absence of any membrane components, both to activate a modified Raf protein and to stimulate the MAP kinase cascade appropriately, indicating that homotypic oligomerization may ordinarily act to promote Raf activation in vivo.
Lack of evidence for the activation of the Ras/Raf mitogenic pathway by 14-3-3 proteins in mammalian cells.
TLDR
Overexpression of 14-3-3 zeta cDNA clones in NIH3T3 cells did not result in detectable morphologic transformation even when co-transfected with plasmids encoding Raf and/or Ras proteins, arguing against a critical regulatory role of the 14- 3-3 proteins in the Raf mitogenic pathway.
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