RhoA Signaling

RhoA is a member of the Ras superfamily of small GTPases that plays a central role in diverse biological processes such as actin cytoskeleton organization, microtubule dynamics, gene transcription, oncogenic transformation, cell cycle progression, adhesion and epithelial wound repair. The activation state of RhoA is controlled by regulatory proteins such as GEFs which catalyze the exchange of GDP for GTP thereby activating Rho, GDIs which inhibit the release of GDP to keep Rho inactive, and GAPs which increase the rate at which Rho hydrolyzes GTP and becomes inactivated.RhoA is activated by a variety of growth factors, cytokines, adhesion molecules, hormones, integrins, G-proteins and other biologically active substances. The major activator of RhoA are GPCRs which use Gα11, Gα12 or Gαi for signal transduction. These GPCRs include receptors for LPA and certain hormones. EphA receptors also directly activate RhoA through Ephexin. IGF activates RhoA indirectly by binding IGF1R which forms a complex with LARG.A number of proteins have been identified as targets of RhoA, which include the PAK family kinases, ROCK family kinases, MBS of myosin PPtase, PKN/PRK-1, Rhophilin, Rhotekin, Citron, and GDIA. RhoA is important for the organization of stress fibers and also in the regulation of actinomyosin contractility through myosin PPtase and MLCP phosphorylation through ROCK. ROCK family kinases also activate LIMK which phosphorylates and inactivates cofilin and regulates actin cytoskeletal reorganization. ROCKs phosphorylate Ezrin/Villin, Radixin and Moesin (ERM) proteins in vitro. ROCKs can also phosphorylate the sodium-hydrogen exchanger, NHE1, which interacts with ERM proteins both directly and via EBP50. Both Rac and RhoA bind to and activate PIP5K which increases the amount of PIP2 and activation of ERM proteins.Besides ROCK, other important targets of RhoA include FAK, PRK-1/ PKN1, BORG, Citron, PLD and GDIA. The GTPase RhoA plays a prominent role in regulating the organization of the cytoskeleton by promoting the assembly of focal adhesions, actin stress fibers and activating FAK. PKN1/PRK-1 and PKN2 are Rho targets involved in endosomal trafficking. Citron is a ROCK related kinase that is critical for cytokinesis and is also implicated in other aspects of cell cycle progression. BORG proteins are Rho targets that connect to septins which polymerize to form filaments involved in cytokinesis in yeast and mammalian cells. RhoA and Rac are also implicated in the regulation of PLD. PLD catalyzes the hydrolysis of phosphatidylcholine to yield phosphatidic acid and choline. Phosphatidic acid is a second messenger involved in membrane remodeling events that are critical to cell growth, such as vesicle trafficking and regulated secretion. RhoA also activates scaffolding proteins such as GDIA, WASP and IRSp53. RhoA binds to Rhophilin and regulates the actin cytoskeleton. RhoA also interacts with a Rho target protein, Rhotekin through the RBD motif. RhoA-dependent signaling is recognized as an essential regulator of vascular function and seems to play an important role in major arterial diseases such as hypertension, atherosclerosis and pulmonary hypertension.