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ROCK and Rho: biochemistry and neuronal functions of Rho-associated protein kinases - PubMed

Review

ROCK and Rho: biochemistry and neuronal functions of Rho-associated protein kinases

André Schmandke et al. Neuroscientist. 2007 Oct.

Abstract

Rho-associated protein kinases (ROCKs) play key roles in mediating the control of the actin cytoskeleton by Rho family GTPases in response to extracellular signals. Such signaling pathways contribute to diverse neuronal functions from cell migration to axonal guidance to dendritic spine morphology to axonal regeneration to cell survival. In this review, the authors summarize biochemical knowledge of ROCK function and categorize neuronal ROCK-dependent signaling pathways. Further study of ROCK signal transduction mechanisms and specificities will enhance our understanding of brain development, plasticity, and repair. The ROCK pathway also provides a potential site for therapeutic intervention to promote neuronal regeneration and to limit degeneration.

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Figures

Fig. 1
Fig. 1

A, General structure of RhoGTPases (adapted from Ridley 2006), and B, Posttranslational modification of RhoA CAAX-Box by geranylgeranyl-prenylation, proteolysis, and C, Methylation. NE = N-terminal extension in some RhoGTPases; ED = effector domain; GR = GTP/GDP-binding regions; AD = additional domains in RhoBTB; HR = hypervariable region (varies in length for different RhoGTPases); CB = CAAX-Box; N = N-terminal end; C = C-terminal end; GG = geranylgeranyl residue; PS = proteolysis site; R = rest of protein N-terminal of CAAX-Box; CLVL = amino acids Cys, Leu, Val, Leu (note: even though S and O are atoms belonging to Cys, they are shown separately in order to visualize the posttranslational bonds).

Fig. 2
Fig. 2

Structure of ROCKI/ROCKII and regulatory binding sites. The upper and lower numbers represent the amino acids of ROCKI and ROCKII, respectively. The following major domains are shown: the catalytic kinase domain (KD), the pleckstrin-homology domain (PHD) that encompasses a cysteine-rich domain (CRD), and the Rho binding domain (RBD) situated within the coiled-coil region. RhoA activates ROCKs by binding to the RBD, whereas Gem and RhoE/Rnd3 inactivate ROCKI preferably by binding to the CCR and KD, respectively. Rad was found to inactivate ROCKII preferably by binding to its CCR. N = N-terminal end; C = C-terminal end.

Fig. 3
Fig. 3

Crystal structure of ROCKI interaction with RhoA (adapted from Dvorsky and others 2004). Shown in the figures are complexes between human ROCKI-RBDs (residues 947-1015; labeled green and brown) and the truncated forms of human RhoA (residues 1-181; labeled magenta and cyan) bound to the nonhydrolyzable GTP analogue Gpp (NH)p (stabilized by Mg2 ). A-D, Display of the complex of two RhoA molecules and two ROCKI molecules from different angles. The close up in B shows the area of ROCKI-RBD/RhoA interaction. The same perspective, only turned 180 degrees around the helix-axis, is employed in E and F, where the residues of ROCKI-RBD, interacting with RhoA, are labeled yellow. These residues include K999, V1003, N1004, L1006, A1007, and M1010 in the brown-labeled α-helix and L998, Q1001, A1002, and K1005 in the green-labeled α-helix. Whereas A-D are rendered in “worms-style,” E uses the “space-fill-style” and F the “ball-and-stick-style.”

Fig. 4
Fig. 4

Main targets of RhoA and ROCK, involved in organization of the cytoskeleton. Arrows carrying a stop sign symbolize inactivation; arrows without a stop sign indicate activation. Molecules attached to numbered arrows lead to the following effects: 1 = decreased depolymerization of actin filaments; 2 = stress fiber formation and increased contractility; 3 = actin polymerization regulation → contractile ring → cytokinesis; 4 = also involved in formation of contractile ring → cytokinesis; 5 = disrupted actin binding activity/signaling mainly unknown so far; 6 = actin-cytoskeletal reorganization; 7 = assembly of actin filaments (spectrin-actin meshwork beneath plasma membranes); 8 = actin organization and focal adhesions; 9 = disruption of intermediate filaments. ? = pathway that is not yet known; P = phosphorylated molecule; RhoA = Ras homology gene family member A; ROCK = Rho-associated coiled-coil-containing protein kinase; CitK = citron kinase; mDia = mammalian diaphanous; CPI-17 = protein kinase C-potentiated inhibitor of 17 kDa; LIMK1/2 = LIM-domaincontaining protein kinases 1 and 2; MLC = myosin-II regulatory light chain; MLCP = myosin-II regulatory light chain phosphatase; NHE1 = Na+/H+-exchanger-1; FABPs = F-actin binding proteins; ERM = ezrin-radixin-moesin; GFAP = glial fibrillary acidic protein; NF-L = neurofilament protein.

Fig. 5
Fig. 5

GTPase cycle. The guanine nucleotide bound to RhoA determines its activation state. Upstream regulators and downstream effector pathways are shown in relationship to guanine nucleotide binding state. See text for description. GAP = GTPase-activating protein; GDI = guanine nucleotide dissociation inhibitors; GDP = guanosine diphosphate; GEF = guanine nucleotide exchange factor; GTP = guanosine triphosphate.

Fig. 6
Fig. 6

RhoA activation/inactivation in neuronal tissues. Steps in receptor signaling pathways regulating neuronal RhoA are illustrated. See text for description. Dab1 = mammalian disabled 1; Jip1/2 = c-Jun N-terminal kinase (JNK) interacting proteins 1 and 2; EGFR = epidermal growth factor receptor; RTK = receptor tyrosine kinase; GPCR = G-protein-coupled receptor; Robo = roundabout receptor; NgR = Nogo receptor; OMgp = oligodendrocyte-mylein glycoprotein; MAG = myelin-associated glycoprotein; LRP = lipoprotein receptor; Larg = leukemia-associated Rho guanine; GEF = guanine nucleotide exchange factor; GDI = guanine nucleotide dissociation inhibitors; GAP = GTPase-activating protein.

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