The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium

Abstract

Many cellular processes are controlled by small GTPases, which can be activated by guanine nucleotide exchange factors (GEFs). The RhoGEF Trio contains two GEF domains that differentially activate the small GTPases such as Rac1/RhoG and RhoA. These small RhoGTPases are mainly involved in the remodeling of the actin cytoskeleton. In the endothelium, they regulate junctional stabilization and play a crucial role in angiogenesis and endothelial barrier integrity. Multiple extracellular signals originating from different vascular processes can influence the activity of Trio and thereby the regulation of the forementioned small GTPases and actin cytoskeleton. This review elucidates how various signals regulate Trio in a distinct manner, resulting in different functional outcomes that are crucial for endothelial cell function in response to inflammation.

Keywords: Rho-GEF; endothelium; inflammation; small GTPase; vasculature.

Figure 1

Schematic representation of Trio isoforms. The full-length Trio contains a Sec14 domain, several Spectrin repeats, two GEF domains, two S SRC Homology 3 Domains (SH3) and a serine/threonine kinase domain. Other isoforms arise due to alternative splicing and contain a mix of these domains. The pink, purple and turquoise box represent specific amino acids unique to the isoform. The figure was created with BioRender.

Figure 2

Functions of Trio in the endothelium. The two GEF domains of Trio can activate either Rac1/RhoG or RhoA. This activation can induce a multitude of functions, of which actin cytoskeleton remodeling, endothelial barrier regulation, sprouting and adhesion molecule expression enabling leukocyte transendothelial migration are shown here. If TrioGEF is depicted in a faint color, this means that the domain does not play a role in this specific pathway. The figure was created with BioRender.