κB-Ras Proteins Regulate Both NF-κB-Dependent Inflammation and Ral-Dependent Proliferation

• κB-Ras proteins are required for Ral-GAP activity toward Ral GTPases
• κB-Ras proteins negatively regulate both NF-κB and Ral pathways
• κB-Ras proteins act as dual-tumor suppressors, controlling inflammation and tumor growth
• κB-Ras levels are decreased in human cancers, providing a growth advantage

SummaryThe transformation of cells generally involves multiple genetic lesions that undermine control of both cell death and proliferation. We now report that κB-Ras proteins act as regulators of NF-κB and Ral pathways, which control inflammation/cell death and proliferation, respectively. Cells lacking κB-Ras therefore not only show increased NF-κB activity, which results in increased expression of inflammatory mediators, but also exhibit elevated Ral activity, which leads to enhanced anchorage-independent proliferation (AIP). κB-Ras deficiency consequently leads to significantly increased tumor growth that can be dampened by inhibiting either Ral or NF-κB pathways, revealing the unique tumor-suppressive potential of κB-Ras proteins. Remarkably, numerous human tumors show reduced levels of κB-Ras, and increasing the level of κB-Ras in these tumor cells impairs their ability to undergo AIP, thereby implicating κB-Ras proteins in human disease.

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