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The appearance of multicellularity implied the adaptation of signaling networks required for unicellular life to new functions arising in this remarkable evolutionary transition. A hallmark of multicellular organisms is the formation of cellular barriers that compartmentalize spaces and functions. Here we discuss recent findings concerning the role of RhoB in the negative control of Rac1 trafficking from endosomes to the cell border, in order to induce membrane extensions to restore endothelial barrier function after acute contraction. This role closely resembles that proposed for RhoB in controlling single cell migration through Rac1, which has also been observed in cancer cell invasion. We highlight these similarities as a signaling paradigm that shows that endothelial barrier integrity is controlled not only by the formation of cell-cell junctions, but also by a balance between ancestral mechanisms of cell spreading and contraction conserved from unicellular organisms and orchestrated by Rho GTPases.

Endothelial barrier dysfunction underlies chronic inflammatory diseases. In searching for new proteins essential to the human endothelial inflammatory response, we have found that the endosomal GTPase RhoB is up-regulated in response to inflammatory cytokines and expressed in the endothelium of some chronically inflamed tissues. We show that although RhoB and the related RhoA and RhoC play additive and redundant roles in various aspects of endothelial barrier function, RhoB specifically inhibits barrier restoration after acute cell contraction by preventing plasma membrane extension. During barrier restoration, RhoB trafficking is induced between vesicles containing RhoB nanoclusters and plasma membrane protrusions. The Rho GTPase Rac1 controls membrane spreading and stabilizes endothelial barriers. We show that RhoB colocalizes with Rac1 in endosomes and inhibits Rac1 activity and trafficking to the cell border during barrier recovery. Inhibition of endosomal trafficking impairs barrier reformation, whereas induction of Rac1 translocation to the plasma membrane accelerates it. Therefore, RhoB-specific regulation of Rac1 trafficking controls endothelial barrier integrity during inflammation., (© 2016 Marcos-Ramiro et al.)