Unknown

Dataset Information

0

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.

SUBMITTER: Freeman AK 

PROVIDER: S-EPMC3582845 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Freeman Alyson K AK   Ritt Daniel A DA   Morrison Deborah K DK  

Molecular cell 20130124 4


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 i  ...[more]

Similar Datasets

| S-EPMC6557854 | biostudies-other
| S-EPMC8654025 | biostudies-literature
| S-EPMC3075323 | biostudies-literature
| S-EPMC5712250 | biostudies-literature
2024-01-02 | GSE235178 | GEO
| S-EPMC1538552 | biostudies-literature
| S-EPMC2649208 | biostudies-literature
| S-EPMC6345758 | biostudies-literature
| S-EPMC3988223 | biostudies-literature
| S-EPMC4954776 | biostudies-literature