Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling.

Abstract

Raf kinases are essential for normal Ras-Raf-MEK-ERK pathway signaling, and activating mutations in components of this pathway are associated with a variety of human cancers, as well as the related developmental disorders Noonan, LEOPARD, and cardiofaciocutaneous syndromes. Although the Raf kinases are known to dimerize during normal and disease-associated Raf signaling, the functional significance of Raf dimerization has not been fully elucidated. Here, using mutational analysis and a peptide inhibitor, we show that dimerization is required for normal Ras-dependent Raf activation and for the biological function of disease-associated Raf mutants with moderate, low, or impaired kinase activity. However, dimerization is not needed for the function of B-Raf mutants with high catalytic activity, such as V600E-B-Raf. Importantly, we find that a dimer interface peptide can effectively block Raf dimerization and inhibit Raf signaling when dimerization is required for Raf function, thus identifying the Raf dimer interface as a therapeutic target.

• Authors: Alyson K Freeman, Daniel A Ritt, Deborah K Morrison
• Journal: Molecular cell (Mol Cell) Vol. 49 Issue 4 Pg. 751-8 (Feb 21 2013) ISSN: 1097-4164 [Electronic] United States
• PMID: 23352452 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Peptide Fragments
• Platelet-Derived Growth Factor
• Protein Kinase Inhibitors
• Epidermal Growth Factor
• raf Kinases
• ras Proteins

Topics

• Amino Acid Substitution
• Animals
• Cell Line
• Enzyme Activation
• Epidermal Growth Factor (physiology)
• Humans
• MAP Kinase Signaling System
• Mice
• Mutagenesis, Site-Directed
• Mutation, Missense
• Neoplasms (enzymology)
• Peptide Fragments (pharmacology)
• Platelet-Derived Growth Factor (physiology)
• Protein Interaction Domains and Motifs
• Protein Kinase Inhibitors (pharmacology)
• Protein Multimerization
• raf Kinases (antagonists & inhibitors, chemistry, genetics, metabolism)
• ras Proteins (metabolism)