Rho Rhokinase Signaling

RhoA GTPase (RhoA) is a member of the Rho (Ras homologous) family of small GTP-binding proteins that includes Rac, Cdc42, and numerous other members (3, 51, 54). These GTPases transduce signals from extracellular stimuli to intracellular target proteins (effectors) that regulate several complex cellular processes, including reorganization of the actin cytoskeleton, cell contraction, adhesion, migration, gene expression, and growth. RhoA cycles between an inactive GDP-bound and active GTP-bound form that is targeted to cell membranes where it stimulates its downstream effectors. RhoA activity is regulated, in ways that are not yet well understood, by three classes of proteins. It is inhibited by guanosine nucleotide disassociation inhibitors (e.g., Rho GDIa), activated by guanosine nucleotide exchange factors (e.g., p 115-Rho, PDZ-Rho, and LARG GEFs), and inactivated by GTPase-activating proteins (e.g., Graf and pl90-Rho GAP). Many cellular responses to activation of G protein-coupled receptors (GPCR) are mediated via Ga12/13, Gaq, or Gq subunit-dependent stimulation of Rho GEFs and activation of RhoA (51). GPCR-independent signaling to RhoA also occurs and can be mediated by receptor and non-receptor tyrosine kinases and by recruitment of other GTPases (51, 54). Several vasoconstrictors, including ET-1, 5-HT, and thromboxane, activate RhoA in VSMC (19, 52). There is indirect evidence that hypoxia also activates RhoA in VSMC (50, 66) and endothelial cells (63).

Rho-kinase, a serine/threonine protein kinase, is a well-characterized RhoA effector (3,51,54). There are two isoforms of Rho-kinase, Rho-associated coiled coil-forming protein kinase (ROCK) I and II (also named ROKfi and ROKa, respectively), with few known functional differences between them. Other RhoA effectors include mDia1/2, protein kinase N (PKN) (also called PKC-related kinase 1, PRK1), PRK2, PIP5-kinase, citron kinase, rhophilin, rhotekin, phospholipase D, and Kv1.2. Many targets of Rho-kinase have been identified, including the myosin-binding subunit (MBS) of myosin light chain (MLC) phosphatase, myosin phosphatase inhibitor protein CPI-17, MLC, calponin, LIM-kinase, adducin, ERM family proteins, and intermediate filaments.

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