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

Molecular Cell cover, Vol. 49, No. 4, Feb. 21, 2013

About the Cover

The Raf kinases are essential for normal Ras-Raf-MEK-ERK pathway signaling, and activating mutations in components of this pathway are associated with human cancer and the related developmental disorders known as RASopathies. In this issue, Freeman et al. (pp. 751–758) demonstrate that Raf dimerization is required for normal Ras-dependent signaling as well as the function of certain disease-associated Raf mutants. A peptide inhibitor based on the Raf dimer interface, DI1 (superhero), was found to inhibit Raf dimerization (trains colliding) and Raf signaling. This study identifies the Raf dimer interface as a therapeutic target and has important implications for the treatment of human disease states with elevated Ras-Raf-MEK-ERK pathway signaling. Cover art by Allen Kane (Scientific Publications, SAIC-Frederick).

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.

Lab/Branch/Program: 
Laboratory of Cell and Developmental Signaling
Citation: 

Effects of Raf dimerazation and its inhibition on normal and disease-associated Raf signaling. Freeman AK, Ritt DA, and Morrison DK. Mol Cell. 2013 Feb 21;49(4):751-8.

Published Date: 
February, 2013