Inhibition of transcription factor NF-kappaB activation by kappaB-Ras

kappaB-Ras1 and kappaB-Ras2 are two small proteins that display similarity at the amino acid level to Ras-like small GTPases. Although little is known about the function of the kappaB-Ras proteins, they have been shown to interfere with activation of transcription factor NF-kappaB. They accomplish this by binding to IkappaB proteins, natural inhibitors of NF-kappaB, and delaying their stimulus-dependent degradation. In this chapter, we consider the kappaB-Ras proteins in light of their NF-kappaB regulatory properties. Three fundamental questions about kappaB-Ras function are addressed: (1) Does kappaB-Ras regulate NF-kappaB in vivo? (2) Does kappaB-Ras selectively regulate specific NF-kappaB/IkappaB complexes? (3) Does kappaB-Ras function as a true GTPase, that is, with molecular switching properties that correlate with the phosphorylation state of bound guanine nucleotide? Finally, we detail the methods currently used to study the kappaB-Ras proteins as regulators of NF-kappaB activation.