Rho family small gtpases in shear stress signaling

© 2010 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. Fluid shear stress is a major determinant of endothelial cell shape, function, and gene transcription. Shear stress activates several signaling cascades in endothelial cells including the following: opening of K+ and CA+2 channels,1-3 activation of heterotrimeric G proteins,4 production of Nitric Oxide,5 tyrosine phosphorylation of proteins such as Shc, c-src, and focal adhesion kinase (FAK),6,7 activation of MAP kinase pathway, protein kinase C (PKC) and jun C-terminal kinase (JNK),8–10 release of reactive oxygen species (ROS),11 and activation of important transcription factors such as c-fos, c-jun, c-myc and NF-kB.12 The hallmark of the endothelial cell responses to fluid shear stress is the rearrangement of cytoskeleton and the elongation of microfilaments and microtubules in the direction of flow. 13–15 Shear stress can also modulate endothelial monolayer permeability of macromolecules16 and leukocytes from the blood into the underlying tissue, which is an early characteristic of atherosclerotic lesion development. 17 A remarkable number of events stimulated by shear are downstream of small GTPases, and in particular Rho family GTPases. There are at least 150 small GTPases encoded by the human genome. The various subclasses of this superfamily, including Ras, Rho, Arf, Rab and Ran GTPases, have been implicated in almost all aspects on cell biology including proliferation, differentiation, cytoskeletal organization, vesicle trafficking, nucleocytoplasmic transport and gene expression.18,19 All of the small GTPases function as binary ‘molecular switches’ that are active when bound to GTP and inactive when bound to GDP. The regulation of these states is tightly controlled by Guanine nucleotide Exchange Factors (GEFs) which activate the protein by exchanging a GDP for a GTP, and GTPase Activating Proteins (GAPs) which catalyze the hydrolysis of GTP to GDP to inactivate the protein. The Rho family of small GTPases has been found to be critical in endothelial signaling pathways activated by shear stress, and the Rho subclass of GTPases will be the focus in this chapter. Three GTPases; namely, RhoA, Rac1 and Cdc42, are known to be crucial in regulating cell shape changes through the rearrangements of the cytoskeleton,20 but they also have roles in endothelial adhesion, permeability and gene expression which are equally significant. This chapter will describe the well known roles for Rho family small GTPases in morphological and cytoskeletal rearrangements, and then discuss what is known about their roles in permeability and gene transcription in response to shear stress.