The Rho family of small GTPases are intimately involved in cytoskeletal rearrangement and the distribution and assembly intercellular adherens complexes and focal adhesions. We and others have shown that over expression of constitutively active Rac enhances peripheral actin polymerization in the cortical ring . Rac activation induces lamellipodia formation, membrane ruffling, the formation of cortical actin filaments, and the spreading of ECs, whereas inhibition of Rac GTPase leads to increased monolayer permeability and enhances the thrombin-mediated barrier dysfunction response through a variety of signaling proteins. We recently reported the critical importance of Rac GTPase-dependent cortical actin rearrangement in the augmentation of pulmonary endothelial cell (EC) barrier function by sphingosine 1-phosphate (S1P), HGF, shear stress, simvastatins, and oxidized phospholipids. Ligation of cell surface S1P receptors triggers a complex signaling cascade mediated by intracellular G-proteins that activate Rac GTPase and modulate molecular trafficking to and enzymatic activity at the cell periphery, resulting in peripheral cytoskeletal enhancement and the formation of functional adherens junction complexes.
Furthermore, Rac GTPase is essential for translocation of cortactin, an F-actin binding protein that stimulates actin polymerization and stabilizes the filamentous actin network, an event necessary for the peak barrier enhancing response to S1P in vitro . Conversely, dominant negative Rac prevents the translocation of cortactin and subsequent actin polymerization in the cell periphery, and attenuates barrier enhancement by simvastatin, sphingosine 1-phosphate, and shear stress. Src kinase-mediated phosphorylation of cor-tactin alters the binding of cortactin, via its SH-3 domain, to MLCK, a molecule potentially important for the organization of filamentous actin in the cortical ring. Finally, Rac inactivates the actin severing protein, cofilin, in the cell periphery through a signaling cascade involving PAK-1 and LIM kinase. Clearly, multiple signaling proteins contribute to modulate dynamic cytoskeletal arrangements, which play a key role in the maintenance or disruption of endothelial barrier integrity.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.