Small GTPases of the Ras superfamily regulate intestinal epithelial homeostasis and barrier function via common and unique mechanisms

Abstract

The intestinal epithelium forms a stable barrier protecting underlying tissues from pathogens in the gut lumen. This is achieved by specialized integral membrane structures such as tight and adherens junctions that connect neighboring cells and provide stabilizing links to the cytoskeleton. Junctions are constantly remodeled to respond to extracellular stimuli. Assembly and disassembly of junctions is regulated by interplay of actin remodeling, endocytotic recycling of junctional proteins, and various signaling pathways. Accumulating evidence implicate small G proteins of the Ras superfamily as important signaling molecules for the regulation of epithelial junctions. They function as molecular switches circling between an inactive GDP-bound and an active GTP-bound state. Once activated, they bind different effector molecules to control cellular processes required for correct junction assembly, maintenance and remodelling. Here, we review recent advances in understanding how GTPases of the Rho, Ras, Rab and Arf families contribute to intestinal epithelial homeostasis.

Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation

“…On a subcellular level, Rho GTPases represent signaling molecules centrally involved in arrangement of cytoskeletal proteins and epithelial cell dynamics (9)(10)(11)(12)(13). Since their activation preferentially takes place when GTPases are associated with cellular membranes (14,15), function of Rho proteins crucially depends on their intracellular localization (16).…”

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

“…[13][14] Epithelial scattering appears to be no exception; expression of a dominant-negative RhoA mutant prevents HGFinduced scattering, in particular preventing cell-cell detachment that is associated with increased cellular contractility. 11 RhoA is best known as a master regulator of cellular contractility, activating myosin-based tension forces in cells.…”

E-cadherin Is Important for the Maintenance of Intestinal Epithelial Homeostasis Under Basal and Inflammatory Conditions

“…Cell junctions are dynamic structures that continuously need to respond to stimuli that may stabilize or destabilize inter-epithelial cell contacts. Inflammatory cytokines activate mediators of signaling pathways such as small GTPases that destabilize junctions by internalization or proteolysis of junction molecules, including E-cadherin [1][2][3]. Such processing disconnects junctions from the actin cytoskeleton, consequently destabilizing cell contacts that facilitate invasion of pathogens to further trigger inflammation.…”