Loitering with Intent: New Evidence for the Role of BRAF Mutations in the Proliferation of Melanocytic Lesions

Abstract

The discovery that the somatic activating missense mutation T1796A, leading to the substitution of glutamate to valine (V600E—previously known as V599E1) in the kinase domain of BRAF, was found in 66% of human melanomas (Davies et al, 2002) has prompted much excitement in the melanoma community. Since this time there has been a great flurry of papers attempting to determine what this mutation means, both in terms of clinical significance, as well as the biochemical behavior of melanoma cells. As yet, we only have part of the answer, and it seems that BRAF, although important to this disease, is probably part of a more complex story. In biochemical terms, the effects of aberrant RAF activation in cancer are well characterized. BRAF is a key player in the Ras/Raf/MAP/ERK Kinase (MEK)/Extracellular Signal Related Kinase (ERK) pathway—a mitogen-activated protein (MAP) kinase cascade, whose activation is implicated in a host of cancers through its myriad effects upon cell growth, invasion, and survival (reviewed more extensively inSmalley, 2003).