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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Rac GTPase regulates Rho signaling in a broad range of physiological settings and in oncogenic transformation [1-3]. Here, we report a novel mechanism by which crosstalk between Rac and Rho GTPases is achieved. Activated Rac1 binds directly to p190B Rho GTPase-activating protein (RhoGAP), a major modulator of Rho signaling. p190B colocalizes with constitutively active Rac1 in membrane ruffles. Moreover, activated Rac1 is sufficient to recruit p190B into a detergent-insoluble membrane fraction, a process that is accompanied by a decrease in GTP-bound RhoA from membranes. p190B is recruited to the plasma membrane in response to integrin engagement [4]. We demonstrate that collagen type I, a potent inducer of Rac1-dependent cell motility in HeLa cells, counteracts cytoskeletal collapse resulting from overexpression of wild-type p190B, but not that resulting from overexpression of a p190B mutant specifically lacking the Rac1-binding sequence. Furthermore, this p190B mutant exhibits dramatically enhanced RhoGAP activity, consistent with a model whereby binding of Rac1 relieves autoinhibition of p190B RhoGAP function. Collectively, these observations establish that activated Rac1, through direct interaction with p190B, modulates subcellular RhoGAP localization and activity, thereby providing a novel mechanism for Rac control of Rho signaling in a broad range of physiological processes.
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PMID:Coordination of Rho and Rac GTPase function via p190B RhoGAP. 1894 7

The Vibrio parahaemolyticus type III effector VopS is implicated in cell rounding and the collapse of the actin cytoskeleton by inhibiting Rho guanosine triphosphatases (GTPases). We found that VopS could act to covalently modify a conserved threonine residue on Rho, Rac, and Cdc42 with adenosine 5'-monophosphate (AMP). The resulting AMPylation prevented the interaction of Rho GTPases with downstream effectors, thereby inhibiting actin assembly in the infected cell. Eukaryotic proteins were also directly modified with AMP, potentially expanding the repertoire of posttranslational modifications for molecular signaling.
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PMID:AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling. 1903 3

The G alpha subunits of the G(12) family of heterotrimeric guanine nucleotide-binding proteins (G proteins), defined by G alpha(12) and G alpha(13), have many cellular functions in common, including stimulation of stress fiber formation and focal adhesion assembly via the small GTPase RhoA activation. We and others previously showed that G alpha(12) and G alpha(13) mediate neurite retraction in neuronal cell lines, but their roles in primary cultured neurons have not been adequately understood. Here, we found that expression of constitutively active mutants of G alpha(12) or G alpha(13) caused growth cone collapse dependent on Rho-kinase activity in hippocampal neurons. The stimulation of thrombin and lysophosphatidic acid (LPA) receptors, which have been thought to selectively couple to G alpha(12) and G alpha(13), respectively, caused growth cone collapse and suppressed axon branching dependent on Rho-kinase activity in hippocampal neurons. Thrombin- and LPA-induced growth cone collapse was suppressed by both single knockdown of G alpha(12) and G alpha(13) with short hairpin RNAs and this suppression was augmented by double knockdown of both G alpha(12) and G alpha(13). These results suggest that thrombin and LPA receptors couple to both G alpha(12) and G alpha(13) for growth cone collapse.
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PMID:Lysophosphatidic acid and thrombin receptors require both G alpha12 and G alpha13 to regulate axonal morphology in hippocampal neurons. 1904 2

Colchicine and nocodazole, both established microtubule disruptors, are useful tools to investigate cytoskeletal-dependent signaling cascades and the associated downstream transcriptional targets. Since cytoskeletal events impact pathophysiologic consequences in the vascular system, the signaling requirements underlying colchicine-stimulated expression of PAI-1 and CTGF, two prominent cell deformation-sensitive fibrosis-initiating proteins, were evaluated in vascular smooth muscle cells. Microtubule disruption rapidly induced EGFR transactivation (at the src kinase-sensitive EGFR(Y845) site) in a ROS-dependent manner. Genetic deficiency of EGFR, inhibition of EGFR signaling with AG1478 or introduction of a kinase-deficient EGFR construct effectively blocked colchicine-stimulated PAI-1 and CTGF expression. MEK/ERK involvement downstream of ROS generation was critical for PAI-1, but not CTGF, expression following cytoskeletal perturbation suggesting bifurcation of signaling pathways downstream of EGFR activation. Colchicine also stimulated SMAD2/3 phosphorylation by a Rho/ROCK-dependent mechanism independent of TGF-beta1 release or receptor activity. Rho/ROCK signaling initiated by tubulin network collapse was required for both CTGF and PAI-1 induction. Colchicine-initiated SMAD3 phosphorylation, however, was essential for PAI-1, but not CTGF, expression further highlighting divergence of signaling events downstream of Rho/ROCK that mediate microtubule deformation-associated changes in profibrotic gene transcription.
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PMID:Differential requirement for MEK/ERK and SMAD signaling in PAI-1 and CTGF expression in response to microtubule disruption. 1924 54

LINGO-1 is a component of the tripartite receptor complexes, which act as a convergent mediator of the intracellular signaling in response to myelin-associated inhibitors and lead to collapse of growth cone and inhibition of neurite extension. Although the function of LINGO-1 has been intensively studied, its downstream signaling remains elusive. In the present study, a novel interaction between LINGO-1 and a serine-threonine kinase WNK1 was identified by yeast two-hybrid screen. The interaction was further validated by fluorescence resonance energy transfer and co-immunoprecipitation, and this interaction was intensified by Nogo66 treatment. Morphological evidences showed that WNK1 and LINGO-1 were co-localized in cortical neurons. Furthermore, either suppressing WNK1 expression by RNA interference or overexpression of WNK1-(123-510) attenuated Nogo66-induced inhibition of neurite extension and inhibited the activation of RhoA. Moreover, WNK1 was identified to interact with Rho-GDI1, and this interaction was attenuated by Nogo66 treatment, further indicating its regulatory effect on RhoA activation. Taken together, our results suggest that WNK1 is a novel signaling molecule involved in regulation of LINGO-1 mediated inhibition of neurite extension.
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PMID:LINGO-1 interacts with WNK1 to regulate nogo-induced inhibition of neurite extension. 1976 2

Lesioned central nervous system (CNS) axons fail to regenerate because of limited availability of neurotrophic factors (NTF) to promote neuron survival and drive axon regeneration through an environment rich in multiple myelin- and non myelin-derived axon growth inhibitory ligands that initiate growth cone collapse through the Rho/Rho kinase (ROCK) signalling pathway. However, pharmacological inhibition of Rho and ROCK promotes neurite outgrowth in PC12, Ntera-2 cells and embryonic/early postnatal neurons in culture. We have used our well-characterised CNS myelin-inhibited adult rat retinal culture model to show that Y27632 only promotes disinhibited neurite outgrowth if RGC are co-stimulated with ciliary neurotrophic factor (CNTF). Y27632 in CNTF-stimulated retinal cultures promotes optimal RGC neurite outgrowth at 10 muM concentrations, while higher concentrations negatively correlate with RGC neurite outgrowth and survival. Raising the levels of cAMP in Y27632-treated retinal cultures also promotes significant RGC neurite outgrowth, an effect that is potentiated by the further inclusion of CNTF. Our results suggest that Y27632-induced ROCK inhibition promotes robust disinhibited axon regeneration of adult neurons only when growth promoting factors are added and/or cAMP levels are raised.
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PMID:ROCK inhibition promotes adult retinal ganglion cell neurite outgrowth only in the presence of growth promoting factors. 1952 75

Macropinocytosis is a type of poorly characterized fluid-phase endocytosis that results in formation of relatively large vesicles. We report that Sonic hedgehog (Shh) protein induces macropinocytosis in the axons through activation of a noncanonical signaling pathway, including Rho GTPase and nonmuscle myosin II. Macropinocytosis induced by Shh is independent of clathrin-mediated endocytosis but dependent on dynamin, myosin II, and Rho GTPase activities. Inhibitors of macropinocytosis also abolished the negative effects of Shh on axonal growth, including growth cone collapse and chemorepulsive axon turning but not turning per se. Conversely, activation of myosin II or treatment of phorbol ester induces macropinocytosis in the axons and elicits growth cone collapse and repulsive axon turning. Furthermore, macropinocytosis is also induced by ephrin-A2, and inhibition of dynamin abolished repulsive axon turning induced by ephrin-A2. Macropinocytosis can be induced ex vivo by high Shh, correlating with axon retraction. These results demonstrate that macropinocytosis-mediated membrane trafficking is an important cellular mechanism involved in axon chemorepulsion induced by negative guidance factors.
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PMID:Negative guidance factor-induced macropinocytosis in the growth cone plays a critical role in repulsive axon turning. 1971 Mar 2

The semaphorin 4D (Sema4D) receptor plexin-B1 constitutively interacts with particular Rho guanine nucleotide exchange factors (RhoGEFs) and thereby mediates Sema4D-induced RhoA activation, a process which involves the tyrosine phosphorylation of plexin-B1 by ErbB-2. It is, however, unknown how plexin-B1 phosphorylation regulates RhoGEF activity. We show here that activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation creates docking sites for the SH2 domains of phospholipase Cgamma (PLCgamma). PLCgamma is thereby recruited into the plexin-B1 receptor complex and via its SH3 domain activates the Rho guanine nucleotide exchange factor PDZ-RhoGEF. PLCgamma-dependent RhoGEF activation is independent of its lipase activity. The recruitment of PLCgamma has no effect on the R-Ras GTPase-activating protein activity of plexin-B1 but is required for Sema4D-induced axonal growth cone collapse as well as for the promigratory effects of Sema4D on cancer cells. These data demonstrate a novel nonenzymatic function of PLCgamma as an important mechanism of plexin-mediated signaling which links tyrosine phosphorylation of plexin-B1 to the regulation of a RhoGEF protein and downstream cellular processes.
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PMID:Semaphorin 4D signaling requires the recruitment of phospholipase C gamma into the plexin-B1 receptor complex. 1980 22

Members of the plasticity-related gene (PRG1-4) family are brain-specific integral membrane proteins and implicated in neuronal plasticity, such as filopodia formation and axon growth after brain lesion. Here we report on the cloning of a novel member of the PRG family, PRG5, with high homologies to PRG3. PRG5 is regulated during brain and spinal cord development and is exclusively allocated within the nervous system. When introduced in neurons, PRG5 is distributed in the plasma membrane and induces filopodia as well as axon elongation and growth. Conversely, siRNA mediated knockdown of PRG5 impedes axon growth and disturbs filopodia formation. Here we show that PRG5 induces filopodia growth independently of Cdc42. Moreover, axon collapse and RhoA activation induced by LPA and myelin-associated neurite inhibitor Nogo-A is attenuated in the presence of PRG5, although direct activation of the RhoA-Rho-PIP5K kinase pathway abolishes PRG5 -formed neurites. Thus, we describe here the identification of a novel member of the PRG family that induces filopodia and axon elongation in a Cdc42-independent manner. In addition, PRG5 impedes brain injury-associated growth inhibitory signals upstream of the RhoA-Rho kinase pathway.
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PMID:Plasticity-related gene 5 (PRG5) induces filopodia and neurite growth and impedes lysophosphatidic acid- and nogo-A-mediated axonal retraction. 2003 6

Semaphorins are a family of secreted and membrane-bound proteins known as axonal pathfinders. Sema4A, a member of class 4 semaphorins, induces growth cone collapse of hippocampal neurons. The binding of Sema4A to growth cones indicates the presence of receptors transmitting signals through the intracellular effectors to induce growth cone collapse in hippocampal neurons. Transfection experiments of the candidate receptor genes into COS-7 cells demonstrated that Sema4A binds to axonal guidance receptors Plexin-B1, -B2 and -B3. To identify the functional Sema4A receptor and the signal transduction machinery, COS-7 cell contraction assay was performed, in which intracellular signal transmission induced by Sema4A triggered cell contraction. Expression vectors encoding plexins and Rnd1, a Rho family GTPase, were transfected into COS-7 cells, and a proportion of contracted cells among the transfectants was determined after incubation with Sema4A. The results demonstrated that the combination of Rnd1 and Plexin-B1, -B2 or -B3 induced significant cell contraction, indicating that B-type plexins transmit an intracellular signal of Sema4A through Rnd1. To further study the mechanism of B-type plexin-mediated signaling in Sema4A-induced growth cone collapse, mouse hippocampal neurons transfected with a control or expression plasmid encoding a constitutively active mutant of R-Ras (R-RasQL) were stimulated with Sema4A, followed by the assessment of growth cone collapse. Expression of R-RasQL significantly blocked Sema4A-induced growth cone collapse in the hippocampal neurons compared with the control plasmid. Sema4A thus induces growth cone collapse through the down-regulation of R-Ras activity in mouse hippocampal neurons.
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PMID:Sema4A induces cell morphological changes through B-type plexin-mediated signaling. 2004 31


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