Rho protein GTPases and their interactions with NFκB: crossroads of inflammation and matrix biology

The RhoGTPases, with RhoA, Cdc42 and Rac being major members, are a group of key ubiquitous proteins present in all eukaryotic organisms that subserve such important functions as cell migration, adhesion and differentiation. The NF kappa B (nuclear factor kappa B) is a family of constitutive and inducible transcription factors that through their diverse target genes, play a major role in processes such as cytokine expression, stress regulation, cell division and transformation. Research over the past decade has uncovered new molecular links between the RhoGTPases and the NF kappa B pathway, with the RhoGTPases playing a positive or negative regulatory role on NF kappa B activation depending on the context. The RhoA-NF kappa B interaction has been shown to be important in cytokine-activated NF kappa B processes, such as those induced by TNF alpha (tumour necrosis factor alpha). On the other hand, Rac is important for activating the NF kappa B response downstream of integrin activation, such as after phagocytosis. Specific residues of Rac1 are important for triggering NF kappa B activation, and mutations do obliterate this response. Other upstream triggers of the RhoGTPase-NF kappa B interactions include the suppressive p120 catenin, with implications for skin inflammation. The networks described here are not only important areas for further research, but are also significant for discovery of targets for translational medicine.