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Negative regulation of the serine/threonine kinase B-Raf by Akt.

B-Raf contains multiple Akt consensus sites located within its amino-terminal regulatory domain. One site, Ser(364), is conserved with c-Raf but two additional sites, Ser(428) and Thr(439), are unique to B-Raf. We have investigated the role of both the conserved and unique phosphorylation sites in the regulation of B-Raf activity in vitro and in vivo. We show that phosphorylation of B-Raf by Akt occurs at multiple residues within its amino-terminal regulatory domain, at both the conserved and unique phosphorylation sites. The alteration of the serine residues within the Akt consensus sites to alanines results in a progressive increase in enzymatic activity in vitro and in vivo. Furthermore, expression of Akt inhibits epidermal growth factor-induced B-Raf activity and inhibition of Akt with LY294002 up-regulates B-Raf activity, suggesting that Akt negatively regulates B-Raf in vivo. Our results demonstrate that B-Raf activity can be negatively regulated by Akt through phosphorylation in the amino-terminal regulatory domain of B-Raf. This cross-talk between the B-Raf and Akt serine/threonine kinases is likely to play an important role in modulating the signaling specificity of the Ras/Raf pathway and in promoting biological outcome.

Pubmed ID: 10869359


  • Guan KL
  • Figueroa C
  • Brtva TR
  • Zhu T
  • Taylor J
  • Barber TD
  • Vojtek AB


The Journal of biological chemistry

Publication Data

September 1, 2000

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM51586

Mesh Terms

  • Amino Acid Sequence
  • Cell Line
  • Consensus Sequence
  • Enzyme Activation
  • Humans
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf