Hematopoietic stem/progenitor cells (HSPCs) maintain the hematopoietic system by balancing their self-renewal and differentiation events. Hematopoietic stem cells also migrate to various sites and interact with their specific microenvironment to maintain the integrity of the system. Rho GTPases have been found to control the migration of hematopoietic cells and other cell types. Although the role of RAC1, RAC2 and CDC42 has been studied, the role of RHOA in human hematopoietic stem cells is unclear. By utilizing constitutively active and dominant negative RHOA, we show that RHOA negatively regulates both in vitro and in vivo migration and dominant negative RHOA significantly increased the migration potential of human HSC/HPCs. Active RHOA expression favors the retention of hematopoietic stem/progenitor cells in the niche rather than migration and was found to lock the cells in the G0 cell cycle phase thereby affecting their long-term self-renewal potential. The current study demonstrates that down
Buy our Recombinant Human RhoA protein. Ab91068 is a full length protein produced in Escherichia coli and has been validated in SDS-PAGE. Abcam provides free…
A pair of adhesion receptors work together to fine-tune suppression of RhoA and promote membrane protrusion, say Bass et al.. During cell migration, the actin cytoskeleton regulator, RhoA, must be alternately inhibited (to allow the leading membrane edge to protrude) and reactivated (to pull up the trailing end of the cell from behind). Inhibition occurs when a receptor called α5β1 integrin, which binds to the extracellular matrix protein, fibronectin, triggers phosphorylation of a RhoA inhibitor called p190RhoGAP-A (p190-A). Another fibronectin receptor, syndecan-4, colocalizes with integrin during RhoA inhibition, but whether this second receptor contributes to inhibition was unknown.. By treating cells with fragments of fibronectin that bound to syndecan-4 but not integrin, the authors showed that syndecan-4 triggered transient relocation of p190-A to the membrane, which correlated with reduced RhoA activity. Syndecan-4 is known to activate PKCα, and exogenous activation of PKCα is known ...
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a regulator of cell migration. The encoded protein appears to function in the RhoA (ras homolog gene family, member A)-Dia1 (diaphanous homolog 1) signal transduction pathway. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010 ...
Rhoc - Rhoc (GFP-tagged) - Mouse ras homolog gene family, member C (Rhoc) available for purchase from OriGene - Your Gene Company.
Rhoc - Rhoc (untagged ORF) - Rat ras homolog gene family, member C (Rhoc), (10 ug) available for purchase from OriGene - Your Gene Company.
The major finding of this study is that inhibition of either RhoA or Rho kinase reduced VEGF-induced endothelial migration and angiogenesis in vitro and abolished the accompanying growth factor-induced changes in the endothelial cytoskeleton. Furthermore, we show that VEGF induces a modest RhoA activation.. Stimulation of endothelial monolayers with VEGF induced the formation of SFs in accordance with other reports.6,39⇓ These SFs were formed rapidly and were maintained for at least 3 hours. They probably exist much longer. Cohen et al40 reported the expression of SFs in ECs 45 hours after VEGF treatment. In Swiss 3T3 cells, transfection of constitutive active Rho kinase results in the formation of SFs and is prevented by inhibition of Rho kinase.20,41⇓ In the present study, we show that Rho kinase is also involved in VEGF-induced cytoskeletal changes in ECs.. Our study provides evidence that VEGF induces RhoA activity. This enhanced RhoA activation is accompanied by recruitment of RhoA to ...
This is a common rationalization used by creationists, but it simply doesnt hold any water. Many proteins are highly conserved in most organisms in terms of their function, and so theres no reason why the Aplysia RhoA protein should be any different from the mouse RhoA or the human RhoA. If one were to take mouse RhoA and express it in African clawed frogs, the protein would still be functional. So theres no real reason for a putative magic designer to make mouse RhoA resemble Rat RhoA more closely than mouse RhoA resembles human RhoA. Likewise, theres no reason why mouse RhoA should be closer to human RhoA than to frog RhoA. In fact, many differences that exist in the sequences of certain genes are neutral, i.e. they do not alter the function. Therefore, theres no reason why there should be fewer neutral substitutions between a human and chimpanzee gene than between a human and a frog ...
To confirm the morphological effects of 5-HT6Rs transfected in neuronal cells, we finally examined whether the activation of neuronal 5-HT6Rs produces effects on RhoA activities. To perform RhoA activity assay as shown in Fig. 2, we carried immunoblot analysis using cultured cortical neurons for sufficient amount of sample proteins. Here, we showed that 5-HT6R activation by ST1936 significantly increased RhoA-GTP level, which was significantly blocked by the pretreatment with SB258585 in cultured neurons (Figs. 4A and 4B). As downstream targets of Rho proteins, RhoA proteins can also affect actin polymerization by regulating cofilin via Rho-ROCK-LIMK-cofilin pathway (Lin et al., 2003). Therefore, we further executed whether the activation of 5-HT6Rs modulates cofilin activities as a downstream target of RhoA. As shown in Figs. 4C and 4D, we observed that treatment with ST1936 significantly increased phosphorylation of cofilin, which was also significantly blocked by SB258585 in cultured neurons. ...
To confirm the morphological effects of 5-HT6Rs transfected in neuronal cells, we finally examined whether the activation of neuronal 5-HT6Rs produces effects on RhoA activities. To perform RhoA activity assay as shown in Fig. 2, we carried immunoblot analysis using cultured cortical neurons for sufficient amount of sample proteins. Here, we showed that 5-HT6R activation by ST1936 significantly increased RhoA-GTP level, which was significantly blocked by the pretreatment with SB258585 in cultured neurons (Figs. 4A and 4B). As downstream targets of Rho proteins, RhoA proteins can also affect actin polymerization by regulating cofilin via Rho-ROCK-LIMK-cofilin pathway (Lin et al., 2003). Therefore, we further executed whether the activation of 5-HT6Rs modulates cofilin activities as a downstream target of RhoA. As shown in Figs. 4C and 4D, we observed that treatment with ST1936 significantly increased phosphorylation of cofilin, which was also significantly blocked by SB258585 in cultured neurons. ...
Rho GTPases are overexpressed in a variety of human tumors contributing to both tumor proliferation and metastasis. Recently, several studies demonstrate an essential role of transcriptional regulation in Rho GTPases-induced oncogenesis. Herein, we demonstrate that RhoA, Rac1, and Cdc42 promote the expression of cyclooxygenase-2 (COX-2) at the transcriptional level by a mechanism that is dependent on the transcription factor nuclear factor-{kappa}B (NF-{kappa}B), but not Stat3, a transcription factor required for RhoA-induced tumorigenesis. With respect to RhoA, this effect is dependent on ROCK, but not PKN. Treatment of RhoA-, Rac1-, and Cdc42-transformed epithelial cells with Sulindac and NS-398, two well-characterized nonsteroid antiinflammatory drugs (NSAIDs), results in growth inhibition as determined by cell proliferation assays. Accordingly, tumor growth of RhoA-expressing epithelial cells in syngeneic mice is strongly inhibited by NS-398 treatment. The effect of NSAIDs over RhoA-induced ...
When DArcy Wentworth Thompsons On Growth and Form was published 100 years ago, it raised the question of how biological forms arise during development and across evolution. In light of the advances in molecular and cellular biology since then, a succinct modern view of the question states: how do genes encode geometry? Our new special issue is packed with articles that use mathematical and physical approaches to gain insights into cell and tissue patterning, morphogenesis and dynamics, and that provide a physical framework to capture these processes operating across scales.. Read the Editorial by guest editors Thomas Lecuit and L. Mahadevan, as they provide a perspective on the influence of DArcy Thompsons work and an overview of the articles in this issue.. ...
Although high RhoA-ROCK activity clearly suppresses AIG, the evidence does not fully exclude the possibility that p120s role might be independent of Rac1 and Src signaling pathways, as is clearly the case with H-Ras. For example, Rac1 and Src might normally suppress RhoA-ROCK activity via p120-independent mechanisms that are then unable to compensate for elevated RhoA-ROCK activity caused separately by p120 ablation. It is worth noting, however, that the effects of p120 ablation are not so potent as to be insurmountable, as indicated by the data on H-Ras. Regardless of the exact mechanism, the ultimate effects of both Rac1 and Src on the RhoA-ROCK pathway and on AIG are clearly dependent on p120.. Interestingly, although H-Ras did not require p120, its ability to induce AIG nonetheless depended on suppression of the ROCK-LIMK cascade and activation of cofilin (Fig. 5). Ras has been shown previously to inhibit ROCK by at least three different cell type-specific mechanisms, including ...
Cytoskeletons pulldown assay kits are the most comprehensive kits available, rhoA protein, rac1 GLISA, cdc42 pulldown, small g-proteins, gtpase, cell motility, pulldown, activation assay, cell shape, lamellipodia, filopodia, microspikes, focal adhesions, ras p21, h-ras, k-ras, arf1, arf6, cytoskeleton, gtpase protein, g-lisa, small g-protein assay, rho pulldown, rhoa pulldown, rho activation assay, rhoa activation assay.
The RhoA-binding kinase (ROK) is one of the target kinases of RhoA and is known to play a critical role in regulating cytoskeletal rearrangement in cells. ROK translocates to the plasma membrane fract
The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1 ...
1CXZ: The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1.
Background: Ras homolog gene family member A (RhoA) is involved in Wnt-5a-induced migration of gastric and breast cancer cells. We investigated the roles of RhoA and Wnt-5a in ovarian carcinoma. Methods: RhoA and Wnt-5a mRNA and protein expression in normal fallopian tube epithelium, benign tumors, primary ovarian carcinomas, and metastatic omentum were quantified. RhoA or Wnt-5a was knocked down in OVCAR3 ovarian carcinoma cells using siRNAs and cell phenotype and expression of relevant molecules were assayed. Results: RhoA and Wnt-5a mRNA and protein expression were found to be significantly higher in metastatic omentum than in ovarian carcinomas, benign tumors, and normal fallopian tube epithelium (p < 0.05), and positively associated with differentiation and FIGO staging (stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05). RhoA and Wnt-5a expression were positively correlated in ovarian carcinoma (p = 0.001, R2 = 0.1669). RhoA or Wnt-5a knockdown downregulated RhoA and Wnt-5a
The small GTPase RhoA increases smooth muscle contractility, and IQGAP1 has previously been shown to bind RhoA (9). Consistent with a pattern of increased RhoA activation, MLC phosphatase phosphorylation and MLC phosphorylation were both increased in Iqgap1-/- compared with WT samples (Figure 2D). RhoA-GTP, the active form, was increased in Iqgap1-/- tracheal smooth muscle and in human airway smooth muscle cells with shRNA-mediated IQGAP1 knockdown (Figure 2, E and F, and Supplemental Figure 3A). These data suggest that IQGAP1 normally blunts airway smooth muscle contractility by inhibiting RhoA activation.. Since IQGAP1 is known to act as a protein scaffold (4, 5, 14), we reasoned that IQGAP1 might bind a RhoGAP and RhoA simultaneously, thus enhancing the inhibitory effect of the RhoGAP on RhoA activation. One RhoGAP in particular, p190A-RhoGAP, is well characterized in multiple cell types (15-17), and we found p190A-RhoGAP knockdown to increase RhoA activation in human airway smooth muscle ...
TY - JOUR. T1 - Interaction between the Type III Effector VopO and GEF-H1 Activates the RhoA-ROCK Pathway. AU - Hiyoshi, Hirotaka. AU - Okada, Ryu. AU - Matsuda, Shigeaki. AU - Gotoh, Kazuyoshi. AU - Akeda, Yukihiro. AU - Iida, Tetsuya. AU - Kodama, Toshio. PY - 2015/3/1. Y1 - 2015/3/1. N2 - Vibrio parahaemolyticus is an important pathogen that causes food-borne gastroenteritis in humans. The type III secretion system encoded on chromosome 2 (T3SS2) plays a critical role in the enterotoxic activity of V. parahaemolyticus. Previous studies have demonstrated that T3SS2 induces actin stress fibers in various epithelial cell lines during infection. This stress fiber formation is strongly related to pathogenicity, but the mechanisms that underlie T3SS2-dependent actin stress fiber formation and the main effector have not been elucidated. In this study, we identified VopO as a critical T3SS2 effector protein that activates the RhoA-ROCK pathway, which is an essential pathway for the induction of the ...
article{a0090b47-94ce-453b-9412-f151ac7d6530, abstract = {The intestinal epithelial barrier, which is regulated by the actin cytoskeleton, exhibits permeability changes during inflammation. Here we show that activation of the CysLT(1) receptor by the inflammatory mediator leukotriene D-4 (LTD4) causes a rapid increase in stress-fibre formation in intestinal epithelial cells. This effect was mimicked by cytotoxic necrotising factor-1 (CNF-1)-induced activation of RhoA, overexpression of constitutively active RhoA (L63-RhoA) and phorbol-ester-induced activation of protein kinase C (PKC). In accordance, inhibition of RhoA, by C3 exoenzyme or by dominant-negative RhoA (N19-RhoA), as well as GF109203X-induced inhibition of PKC, suppressed the LTD4-induced stress-fibre formation. Introduction of the dominant-negative regulatory domain of PKCdelta, but not the corresponding structures from PKCalpha, betaII or epsilon, blocked the LTD4-induced stress-fibre formation. Evaluating the relationship between ...
Rho GTPases are master regulators of many immunoreceptors, ranging from receptors required for differentiation and maturation of immune cells and for pathogen recognition to receptors involved in pathogen uptake and the subsequent host signaling responses. Several TLRs induce the activation of the Rho family GTPases Rac, Rho, and Cdc42. Almost every cell type, including professional innate immune cells such as macrophages, neutrophils, and dendritic cells, responds to TLR stimulation by activating Rho GTPases rapidly (8, 20, 31). Similarly, lung epithelial cells induce Rho GTPase activation when they encounter TLR ligands. It seems apparent that RhoA activation depends on the interaction of a specific TLR ligand with its cognate TLR, independently of the connecting adapters or the cellular compartment where TLR signaling occurs. A RhoA FRET probe was used to examine localized RhoA activity at early time points after initiation of TLR2 or TLR3 signaling. After 3-5 min of treatment with the TLR2 ...
Changes in cell morphology are linked to many cellular events including cytokinesis, differentiation, migration and apoptosis. We recently showed that BNIP-Sα induced cell rounding that leads to apoptosis via its BNIP-2 and Cdc42GAP Homology (BCH) domain, but the underlying mechanism has not been determined. Here, we have identified a unique region (amino acid 133-177) of the BNIP-Sα BCH domain that targets RhoA, but not Cdc42 or Rac1 and only the dominant-negative form of RhoA could prevent the resultant cell rounding and apoptotic effect. The RhoA-binding region consists of two parts; one region (residues 133-147) that shows some homology to part of the RhoA switch I region and an adjacent sequence (residues 148-177) that resembles the REM class I RhoA-binding motif. The sequence 133-147 is also necessary for its heterophilic interaction with the BCH domain of the Rho GTPase-activating protein, p50RhoGAP/ Cdc42GAP. These overlapping motifs allow tripartite competition such that ...
TY - JOUR. T1 - BCL6 suppresses RhoA activity to alter macrophage morphology and motility. AU - Pixley, Fiona J.. AU - Xiong, Ying. AU - Yu, Raymond Yick Loi. AU - Sahai, Erik A.. AU - Stanley, E. Richard. AU - Ye, B. Hilda. PY - 2005/5/1. Y1 - 2005/5/1. N2 - BCL6 is a potent transcriptional repressor that plays important roles in germinal center formation, T helper cell differentiation and lymphomagenesis and regulates expression of several chemokine genes in macrophages. In a further investigation of its role in macrophages, we show that BCL6 inactivation in primary bone marrow-derived macrophages leads to decreased polarization, motility and cell spreading accompanied by an increase in peripheral focal complexes, anchored F-actin bundles and cortical F-actin density. These changes were associated with excess RhoA activation. C3 transferase inhibition of RhoA activity reverted the adhesion structure phenotype, which was not affected by Rho kinase inhibitors, suggesting that other downstream ...
Mature thymocytes expressing constitutively active RhoA are hyperresponsive to TCR/CD3 triggering. (A) Analysis of CD3/TCR expression on thymic populations. Thymocytes from NLC and V14RhoA mice were stained for CD4, CD8, and CD3ε. Histograms show expression of CD3 on CD4+CD8+ DP population, CD4+ single positive (CD4 SP), and CD8+ single positive (CD8 SP). Mean fluorescence intensity for CD3 expression is shown in the histograms. (B) TCR-stimulated in vitro proliferation of thymocytes. Total thymocytes from NLC and V14RhoA transgenic mice were prepared as described previously. Proliferation of thymic T cells in response to a range of concentrations of plate-bound anti-CD3 antibody, or a combination of PdBu (5 ng/ml) and ionomycin (0.5 ng/ml), was assessed by the incorporation of [3H]thymidine during the last 12 h of a 36-h assay. Graph shows mean of [3H]thymidine incorporation (± SEM) of triplicate samples. Circles represent proliferation of thymocytes to PdBu plus ionomycin. The experiment ...
Rho family GTPases have received increasing attention as critical regulators of cell function (1). Initially, they were shown to regulate actin dynamics, thereby modulating development, cell migration, immune responses, and cancer cell invasion and metastasis. More recent studies have shown that they are also involved in cell-cell adhesion and cell cycle progression. RhoA is one of the most widely studied of the 22 mammalian members of the family, and the serine-threonine kinase Rho kinase (ROCK) is a major RhoA effector.. RhoA/ROCK has a number of functions in the kidney. RhoA/ROCK enhances Ca2+-dependent vascular smooth muscle contraction, thereby modulating tone (2-4). The potent vasoconstrictor angiotensin II (AngII) activates ROCK in smooth muscle cells. The ROCK inhibitors fasudil and Y-27632 dilate afferent and efferent arterioles and reverse AngII-dependent arteriolar vasoconstriction. At the cellular level, RhoA/ROCK mediates cytoskeletal rearrangement in renal tubule cells, mesangial ...
The precise regulation of intestinal epithelial TJs is crucial to maintaining barrier function between the luminal milieu and the internal environment. Recent studies have revealed an important role for Rho GTPases in regulating TJ structure/function (22, 29). In particular, TJ strand organization has been shown to be altered by constitutively active RhoA and Rac1 mutants (22) and inactivation of GTPases by C. difficile toxins is known to cause redistribution of occludin and ZO-1 from membrane microdomains or membrane rafts (32). As a result, we have further explored the mechanisms whereby paracellular permeability is influenced by this family of mediators and investigated whether the inactivation of a single GTPase (RhoA, Rac1, or Cdc42) has an effect on TJ distribution in such membrane rafts and whether TJ proteins involved in strand formation (such as claudin-1 and -2) are altered in this setting.. Using MDCK cell lines that express constitutively active or dominant-negative RhoA, Rac1, or ...
Rho-family GTPases play a central role in the regulation of neuronal morphogenesis. In growth cones, for example, Rho GTPases transduce extracellular stimuli into structural changes such as filopodia and lamellipodia. Although it is generally accepted that Rac1/Cdc42 and RhoA are positive and negati …
ROCK (Rho-associated protein kinase) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine kinases. ROCKs (ROCK1 and ROCK2) occur in mammals, zebrafish, Xenopus, invertebrates and chicken. Human ROCK1 has a molecular mass of 158 kDa and is a major downstream effector of the small GTPase RhoA. Mammalian ROCK consists of a kinase domain, acoiled-coil region and a Pleckstrin homology (PH) domain, which reduces the kinase activity of ROCKs by an autoinhibitory intramolecular fold if RhoA-GTP is not present. ROCK plays a role in a wide range of different cellular phenomena, as ROCK is a downstream effector protein of the small GTPase Rho, which is one of the major regulators of the cytoskeleton.. ...
The non-receptor tyrosine kinase Src phosphorylates the newly discovered and described GTPase activating protein (GAP) ARHGAP42 that targets RhoA, among other Rho family GTPases, on tyrosine residue 376 which results in activation of ARHGAP42 which in turn de-activates GTP-bound (active) RhoA and correlates with increased cell motility that relies upon dynamic changes in the actin cytoskeleton and focal adhesions, changes involving RhoA signaling.
Our results suggest that Ang II activates RhoA in cardiac myocytes. RhoA mediates Ang II-induced formation of nonstriated sarcomeric actin fibers (premyofibrils), which are distinct from stress fibers, in cardiac myocytes. Considering the existence of multiple downstream target molecules and the pleiotropic functions of Rho as reported in other cell types (References 30, 39, and 4030 39 40 ; see Reference 22 for review), RhoA may play an important role in remodeling processes of the heart caused by Ang II.. Since Rho is a member of the small GTP-binding proteins, activation of Rho could be shown by its increased binding of GTP. However, the guanine nucleotide binding assay or determination of the guanine nucleotide exchange activity for Rho has been technically difficult because the available antibody is not suitable for immunoprecipitating the native form of Rho41 in the presence of Mg2+ (authors unpublished data, 1997). Since Mg2+ is essential for preserving the guanine nucleotide binding of ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
We have shown that RhoA signaling plays a critical role in stretch-induced expression of β-MHC. In addition, the demonstration that inhibition of RhoA/ROCK signaling markedly attenuated stretch-induced FAK activation and that FAK antisense oligonucleotide induced a comparable reduction of stretch-induced expression of β-MHC supports the idea that FAK mediates the influence of RhoA on stretch-induced gene expression in NRVMs. Previous studies showed that RhoA (1, 20, 25, 43) and FAK (22, 38, 39) control expression of the fetal gene atrial natriuretic factor in cardiac myocytes in response to hypertrophic agonists and mechanical stress. Collectively, these data are consistent with a critical role for RhoA/ROCK and FAK signaling in promoting expression of the hypertrophic genetic program by mechanical stress in cardiac myocytes.. The present results also outline a pathway involving RhoA/ROCK and FAK as upstream mediators of stretch-induced ERK1/2 phosphorylation. Additionally, we have ...
Subjecting endothelial cells to short-term increases in shear stress, both in vivo and in vitro, sets off a signaling cascade that results in the alteration of cell morphological features that serves the endothelium in adapting to new flow environments. A major feature of this process is the reorganization of the cytoskeletal network and the development of actin stress fibers. Although the precise signaling mechanism that regulates this process is not fully understood, the temporal regulation of RhoA activity appears to be essential for proper cytoskeletal realignment and adjustment of endothelial cells to changes in shear.19,30,31 Several studies have also demonstrated that shear-induced RhoA activation is secondary to integrin activation; however, the mechanosignaling mechanisms that link integrins to RhoA and actin remodeling remain unclear. Past work from our laboratory17,18 indicates that the shear-induced phosphorylation of MLC, an event that is associated with actin stress fiber ...
Orphan receptor that regulates migration of lymphatic endothelial cells in vitro via the small GTPases RhoA and CDC42 (PubMed:24178298). Regulates B-cell development (By similarity). Seems to signal through G-alpha(q)-proteins (PubMed:22575658).
The goal of this study was to define the AVL-292 AVL-292 role from the Rho category of little GTPases in the β-adrenergic regulation from the Na K-ATPase in alveolar epithelial cells (AEC). not really prevent RhoA activation by ISO. Finally the ISO-mediated Na K-ATPase exocytosis was governed with the Rho-associated kinase (Rock and roll) as […]. Read More ». ...
The President of the National Assembly (Spanish: Presidente de la Asamblea Nacional) is the presiding officer (speaker) of the National Assembly, Venezuelas unicameral legislature. The presidents term coincides with the term of the legislature (five years as per constitutional convention). The post has existed since the election of the first National Assembly in 2000. Before the creation of the National Assembly with the adoption of the 1999 constitution, the countrys legislature was the bicameral Congress, which contained the Senate and the Chamber of Deputies. The last president of the Senate was Luis Alfonso Dávila, and the last president of the Chamber of Deputies was Henrique Capriles Radonski.[1] The current President of the National Assembly, since 5 January 2019, is Juan Gerardo Guaidó Márquez, a member of the Popular Will (VP) party and the Democratic Unity Roundtable coalition.[citation needed] ...
TY - JOUR. T1 - Oxidative species increase arginase activity in endothelial cells through the RhoA/Rho kinase pathway. AU - Chandra, S.. AU - Romero, M. J.. AU - Shatanawi, A.. AU - Alkilany, A. M.. AU - Caldwell, R. B.. AU - Caldwell, R. William. PY - 2012/1/1. Y1 - 2012/1/1. N2 - Background and Purpose NO produced by endothelial NOS is needed for normal vascular function. During diabetes, aging and hypertension, elevated levels of arginase can compete with NOS for available l-arginine, reducing NO and increasing superoxide (O 2 .-) production via NOS uncoupling. Elevated O 2 .- combines with NO to form peroxynitrite (ONOO -), further reducing NO. Oxidative species increase arginase activity, but the mechanism(s) involved are not known. Our study determined the mechanism involved in peroxynitrite and hydrogen peroxide-induced enhancement in endothelial arginase activity. We hypothesized that oxidative species increase arginase activity through PKC-activated RhoA/Rho kinase (ROCK) pathway. ...
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Title:Rho Kinase Inhibitors: Potential Treatments for Diabetes and Diabetic Complications. VOLUME: 18 ISSUE: 20. Author(s):Hong Zhou and Yong-jun Li. Affiliation:Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.. Keywords:RhoA, Rho kinase, inhibitors, diabetes, complications, GTPase, hypertension, coronary vasospasm, stroke, atherosclerosis. Abstract:The small GTPase RhoA and its downstream effector, Rho kinase (ROCK), appear to mediate numerous pathophysiological signals, including smooth muscle cell contraction, actin cytoskeleton organization, cell adhesion and motility, proliferation, differentiation and the expression of several genes. Clinical interest in the RhoA/ROCK pathway has increased, due to emerging evidence that this signaling pathway is involved in the pathogenesis of several diseases, including hypertension, coronary vasospasm, stroke, atherosclerosis, heart failure and diabetes; ROCK is considered an important future ...
In the present study, we have shown that Robo proteins are expressed in cultured OECs and exhibit enriched distribution at the leading edge. A Slit-2 gradient indeed strongly repelled the migration of these cultured OECs. To our knowledge, this is the first guidance factor discovered to repel OEC migration. Because Slit-2 is highly expressed in the apical cells of OE, it is likely that it might help Robo-expressing OECs and olfactory axons migrate out of the OE through chemorepulsion during early development. Slits expressing in the OB might also regulate the stop and scattering of OECs that have arrived at the surface of the OB. OECs have been reported to pioneer the olfactory sensory nerves and provide a conductive substrate for the growth of olfactory sensory axons during development (Tennent and Chuah, 1996; Tisay and Key, 1999). An intriguing possibility is that the guidance of OECs by Slits might contribute to the guidance of axons because of the close interaction between neurons and glia. ...
TY - JOUR. T1 - Lipoxin A4 mediates aortic contraction via rhoa/rho kinase, endothelial dysfunction and reactive oxygen species. AU - Wenceslau, Camilla F.. AU - Mccarthy, Cameron Grant. AU - Szasz, Theodora. AU - Webb, R. Clinton. PY - 2014/3/6. Y1 - 2014/3/6. N2 - Background: Lipoxin A4 (LXA4) is a biologically active product generated from arachidonic acid by lipoxygenase action. The production of lipoxins is enhanced by aspirin through acetylation of cyclooxygenase-2, via a mechanism known as aspirin-triggered lipoxin. LXA4 has both anti-inflammatory and proinflammatory actions, the latter being related with reocclusion and restenosis after coronary angioplasty in patients treated with aspirin. However, little is known of the actions of LXA4 on the vasculature. We hypothesized that LXA4 promotes contractile responses and contributes to endothelial dysfunction. Methods: We used aorta from Wistar rats to assess vascular function. Reactive oxygen species (ROS) production and contractile and ...
To investigate whether cell movement patterns are governed by signals from the environment or whether cell behaviour is intrinsically/cell autonomously regulated, we performed heterochronic grafts. GFP-labelled cells were isolated from the anterior primitive streak of HH3 embryos and grafted into the anterior streak of a HH4 host. Prospective cardiac cells grafted into the HH4 anterior primitive streak behaved appropriately for their new environment, they displayed a narrow migration trajectory and gave rise to paraxial mesoderm, as described previously (Yang et al., 2002) (n=11/11). Conversely, HH4 paraxial mesoderm progenitors grafted into the anterior streak of HH3 host embryos displayed movement trajectories typical for cardiac progenitors and indistinguishable from the HH3 homotypic grafts shown (Fig. 1C-F, Fig. 2A,B; n=11/11, not shown). These experiments demonstrated that cell movement patterns are established by extrinsic cues.. Wnt3a transcripts are highly expressed in the primitive ...
Neuropathy is a major complication that affects nearly half of all patients with diabetes, greatly decreasing their quality of life. Patients experience a wide range of symptoms including pain, numbness, weakness and other morbidities. While its pathogenesis has been the focus of extensive research, there are still few effective treatment options available for this disease. The discovery of novel molecular targets underlying this diabetic neuropathy may lead to the development of new, more effective therapeutics. DLC2, a Rho GTPase-activating protein with specific activity for RhoA, was shown to be involved in pain signaling. Mice deficient for this protein (DLC2-/-) have increased RhoA activity in their peripheral nerves, and have heightened pain responses compared to wild type (DLC2+/+) in acute pain tests, displaying increased sensitivity to noxious thermal and inflammatory stimuli. DLC2-/- mice also show elevated blood glucose levels, lower body weight and increased sensitivity to blood ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Rac1 and RhoA are members of the Rho family of Ras-related proteins and function as regulators of actin cytoskeletal organization, gene expression, and cell cycle progression. Constitutive activation of Rac1 and RhoA causes tumorigenic transformation of NIH 3T3 cells, and their functions may be required for full Ras transformation. The effectors by which Rac1 and RhoA mediate these diverse activities, as well as the interrelationship between these events, remain poorly understood. Rac1 is distinct from RhoA in its ability to bind and activate the p65 PAK serine/threonine kinase, to induce lamellipodia and membrane ruffling, and to activate the c-Jun NH2-terminal kinase (JNK). To assess the role of PAK in Rac1 function, we identified effector domain mutants of Rac1 and Rac1-RhoA chimeric proteins that no longer bound PAK. Surprisingly, PAK binding was dispensable for Rac1-induced transformation and lamellipodium formation, as well as activation of JNK, p38, and serum response factor (SRF). ...
Although it is well understood that Rho GTPase activity is regulated by GEFs, very little is known about the specific role GEFs play in regulating cellular processes, such as migration. Our results show that Asef2 coordinately regulates the activities of Rho family members to promote cell migration by stimulating the rapid turnover of adhesions. Asef2 signaling leads to an overall decrease in the amount of active RhoA, which is crucial for the effect of Asef2 on migration. RhoA induces the formation of stress fibers and can promote the maturation of nascent cell-matrix contacts into large, focal adhesions (Chrzanowska-Wodnicka and Burridge, 1996; Ridley and Hall, 1992; Rottner et al., 1999). Thus, the loss of RhoA activity in GFP-Asef2 stable cells could inhibit the maturation of nascent adhesions and contribute to the more rapid turnover of these structures. These described activities of Rho would be expected to inhibit migration. Indeed, in some cell types, high levels of Rho have been shown ...
RhoA RhoB and RhoC GTPases are over 85% identical at the amino acid level with RhoA and RhoC differing at only one residue (43) across the initial two-thirds of their sequences. substitution of RhoA Val 43 with an Ile was found to significantly promote basal nucleotide exchange activity and enhance GTP-loading in cells. Substitution of Val 43 with an Ile in RhoB negatively affected nucleotide exchange in vitro. Substitution of LY317615 RhoC Ile 43 with a Val increased GEF-catalyzed exchange in vitro. In addition RhoC-I43V was more efficacious at generating ovarian tumor cell invasion through matrigrel than wild-type RhoC RhoC-I43T wild-type RhoA RhoA-V43I or RhoA-V43T GTPases. These results claim that a divergence between RhoA/B and RhoC at residue 43 influences basal and GEF-stimulated nucleotide exchange activity. cells (Stratagene) using glutathione-Sepharose 4B (Amersham Biosciences). Protein had been eluted with free of charge and decreased glutathione in TBSM (50 mM Tris pH 7.0 150 mM NaCl ...
Rho family GTPase subfamily Rnd includes Rnd1/Rho6, Rnd2/Rho7, and Rnd3/RhoE/Rho8. The Rnd subfamily contains Rnd1/Rho6, Rnd2/Rho7, and Rnd3/RhoE/Rho8. These novel Rho family proteins have substantial structural differences compared to other Rho members, including N- and C-terminal extensions relative to other Rhos. Rnd3/RhoE is farnesylated at the C-terminal prenylation site, unlike most other Rho proteins that are geranylgeranylated. In addition, Rnd members are unable to hydrolyze GTP and are resistant to GAP activity. They are believed to exist only in the GTP-bound conformation, and are antagonists of RhoA activity. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation. ...