Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. STKE, 23 March 2004
Vol. 2004, Issue 225, p. tw107
[DOI: 10.1126/stke.2252004TW107]

EDITORS' CHOICE

ONCOGENESIS An Alternate Way to Keep Active

Overactivity of the Ras-Raf-MEK [mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase (ERK) kinase]-ERK signaling pathway, through which numerous cytokines and growth factors regulate cell growth and proliferation, is associated with many cancers. More than 30 single site mutations of the serine-threonine kinase B-Raf (one of three Raf isoforms) have been identified in human cancers, prompting Wan et al. to investigate the mechanisms whereby these mutations--most of which involve the kinase domain--promote oncogenesis. Eighteen of 22 oncogenic B-Raf mutants analyzed yielded increased MEK phosphorylation in vitro compared with that by wild-type B-Raf (WTB-Raf) and, when expressed in COS cells, stimulated ERK phosphorylation and activity. However, three mutants with reduced in vitro kinase activity compared with that of WTB-Raf also activated ERK in COS cells and Xenopus embryos. These "impaired activity" mutants formed complexes with the C-Raf isoform (as did WTB-Raf and mutants with increased kinase activity) and, unlike WTB-Raf, activated C-Raf. The authors used RNA interference to show that C-Raf was necessary for ERK stimulation by the impaired activity mutants, but not by those with increased kinase activity. Structural analysis indicated that the B-Raf activation segment (within which Raf must be phosphorylated for kinase activity) is maintained in an inactive conformation through association with the nucleotide-binding P loop and that most oncogenic mutations were in these two regions. The authors developed a model in which disrupting the association between the P loop and the activation segment led to oncogenic B-Raf activity; impaired activity mutants (whose mutations also affect kinase function) must signal to ERK indirectly through the activation of C-Raf (see also Preview by Hubbard).

P. T. C. Wan, M. J. Garnett, S. M. Roe, S. Lee, D. Niculescu-Duvaz, V. M. Good, Cancer Genome Project, C. M. Jones, C. J. Marshall, C. J. Springer, D. Barford, R. Marais, Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855-867 (2004). [Online Journal]

S. R. Hubbard, Oncogenic mutations in B-Raf: Some losses yield gains. Cell 116, 764-766 (2004). [Online Journal]

Citation: An Alternate Way to Keep Active. Sci. STKE 2004, tw107 (2004).


To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882