Negative regulation of oncogenic Ras signaling by mitogen-activated protein kinase phosphatase-3.

Abstract

Activating mutations in the Ras oncogene are found in ~30% of all human cancers. Ras is a central regulator of intracellular signaling pathways, such as the Raf/MEK1/2/ERK1/2 protein kinase cascade, that modulate cell cycle progression, cell proliferation, and cell survival. Chronic activation of Ras-stimulated pathways is believed to play a key role in cellular transformation, although constitutive activation of Ras alone is not sufficient for tumor development. The goal of these studies is to further understand the biochemical events that occur during carcinogenesis in cells that express activated Ras that make cells susceptible to tumor promoting stimuli. This knowledge is important for the development of new strategies to diagnose, prevent and treat cancer. To date, attempts at developing small molecule inhibitors of oncogenic Ras have been unsuccessful. Therefore, efforts have instead focused on targeting downstream effectors of Ras, such as the Raf/MEK1/2/ERK/12 cascade, or preventing the posttranslational prenylation of Ras that is critical for its function. The aim of these studies is two-fold: 1) to elucidate the signaling events that occur in cells exposed to tumor-promoting stimuli; and 2) to develop tools for the study of prenylation in living cells.