Multiple Signalling Pathways Lead to the Activation of the Nuclear Factor κB by the Rho Family of GTPases

Abstract

Members of the Rho family of small GTPases activate the nuclear factor kappaB (NF-kappaB) (Perona, R., Montaner, S., Saniger, L., Sánchez-Pérez, I., Bravo, R., and Lacal, J. C. (1997), Genes & Dev. 11, 463-475). We have investigated whether different members of the family of exchange factors specific for Rho proteins (Dbl family) could activate the transcription factor NF-kappaB and have explored both their specificity under in vivo conditions and the mechanisms involved. Activated forms of Dbl, Ost, and Vav proteins induce NF-kappaB activation. While the activation induced by the Vav oncogen was efficiently inhibited by a dominant negative mutant of Rac1, the corresponding mutant of Cdc42Hs was able to block selectively NF-kappaB activation mediated by Dbl. Finally, mutants of RhoA and Cdc42Hs, but not that of Rac1, inhibited the activation of NF-kappaB by Ost. Thus, under in vivo conditions, different members of the Dbl family are related to specific Rho GTPases for the regulation of NF-kappaB. Activation of NF-kappaB by Rho or Ras proteins is mutually independent. However, there is a link between the NF-kappaB and the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) cascades since a dominant negative mutant of MEKK1 is able to inhibit NF-kappaB activation induced by Rac1 and Cdc42Hs proteins, but not by RhoA. These results indicate that, in mammalian cells, multiple pathways coexist for the activation of NF-kappaB, some of which are mediated by specific members of the Ras and Rho families of small GTPases.