Effects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling

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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. © 2013 Elsevier Inc.

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Freeman, A. K., Ritt, D. A., & Morrison, D. K. (2013). Effects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling. Molecular Cell, 49(4), 751–758. https://doi.org/10.1016/j.molcel.2012.12.018

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