Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.25 (triphosphatase)
1,529 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homing and engraftment of hematopoietic stem cells (HSCs) to the bone marrow (BM) involve a complex interplay between chemokines, cytokines, and nonpeptide molecules. Extracellular nucleotides and their cognate P2 receptors are emerging as key factors of inflammation and related chemotactic responses. In this study, we investigated the activity of extracellular adenosine triphosphate (ATP) and uridine triphosphate (UTP) on CXCL12-stimulated CD34+ HSC chemotaxis. In vitro, UTP significantly improved HSC migration, inhibited cell membrane CXCR4 down-regulation by migrating CD34+ cells, and increased cell adhesion to fibronectin. In vivo, preincubation with UTP significantly enhanced the BM homing efficiency of human CD34+ cells in immunodeficient mice. Pertussis toxin blocked CXCL12- and UTP-dependent chemotactic responses, suggesting that G-protein alpha-subunits (Galphai) may provide a converging signal for CXCR4- and P2Y-activated transduction pathways. In addition, gene expression profiling of UTP- and CXCL12-treated CD34+ cells and in vitro inhibition assays demonstrated that Rho guanosine 5'-triphosphatase (GTPase) Rac2 and downstream effectors Rho GTPase-activated kinases 1 and 2 (ROCK1/2) are involved in UTP-promoted/CXCL12-dependent HSC migration. Our data suggest that UTP may physiologically modulate the homing of HSCs to the BM, in concert with CXCL12, via the activation of converging signaling pathways between CXCR4 and P2Y receptors, involving Galphai proteins and RhoGTPases.
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PMID:The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration. 1700 51

Cell division cycle 42 (Cdc42), a member of the Rho family of small guanosine triphosphatase (GTPase) proteins, regulates multiple cell functions, including: motility, proliferation, apoptosis, and cell morphology. In order to obtain insight into the role of Cdc42 in meiotic resumption and embryo development, we first evaluated its gene expression levels in mouse oocytes and embryos during in vitro development. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed high-expression levels in GV stage oocytes that steadily decreased up to the 2-cell (2C) stage embryo, and then expression increased during morulae and blastocyst formation. Indirect Immunocytochemistry also showed protein synthesis of CDC42 in the mouse oocytes and early embryos. Introducing small interference RNA (siRNA) of Cdc42 into germinal vesicle stage oocytes or zygotes specifically reduced both mRNA expression and protein synthesis of CDC42 in in vitro developed metaphase II oocytes and early embryos. Meiotic maturation and cytoskeleton assembly were significantly altered following siRNA injection into germinal vesicle stage oocytes. Injection of siRNA into the zygote did not affect cleavage or cell numbers in morulae, but significantly decreased in vitro development to the morula or blastocyst. These findings suggest that gene expression of Cdc42 is involved in meiotic resumption and blastocyst formation in the mouse, possibly through maintaining polarity.
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PMID:Cdc42 is implicated in polarity during meiotic resumption and blastocyst formation in the mouse. 1715 94

Inconsistent results concerning the association of polymorphisms in the MYO9B gene with celiac disease (CD) have been recently published. This gene encodes a myosin with a guanosine-triphosphatase (GTPase)-activating protein domain for the Rho-family of small G proteins, which are involved in cytoskeleton remodeling and therefore potentially involved in intestinal permeability. Functional and positional reasons led us to investigate the role of MYO9B polymorphisms in the Spanish CD population. A case-control study, including 415 CD patients and 433 ethnically matched healthy controls, and a familial study, including parents of 145 of those CD patients, was performed. Six MYO9B variants previously associated with CD were analyzed: rs2305767, rs2279003, rs962917, rs1457092, rs2305765 and rs2305764. No MYO9B variants or MYO9B haplotypes were found associated with CD, either before or after stratification of the patients for the human leucocyte antigen (HLA)-DQ2-positive risk factor. The family study revealed no distorted transmission of the aforementioned MYO9B polymorphisms or haplotypes. Our results support a negligible influence of this gene on CD predisposition.
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PMID:No evidence of association of the MYO9B polymorphisms with celiac disease in the Spanish population. 1717 39

Differentiation of hepatic stellate cells (HSCs) to extracellular matrix- and growth factor-producing cells supports liver regeneration through promotion of hepatocyte proliferation. We show that the neurotrophin receptor p75NTR, a tumor necrosis factor receptor superfamily member expressed in HSCs after fibrotic and cirrhotic liver injury in humans, is a regulator of liver repair. In mice, depletion of p75NTR exacerbated liver pathology and inhibited hepatocyte proliferation in vivo. p75NTR-/- HSCs failed to differentiate to myofibroblasts and did not support hepatocyte proliferation. Moreover, inhibition of p75NTR signaling to the small guanosine triphosphatase Rho resulted in impaired HSC differentiation. Our results identify signaling from p75NTR to Rho as a mechanism for the regulation of HSC differentiation to regeneration-promoting cells that support hepatocyte proliferation in the diseased liver.
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PMID:Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. 1766 15

During cutaneous wound healing, increased proliferation and migration of epidermal keratinocytes is essential for efficient re-epithelialization of the wound and restoration of barrier function to the skin. Although numerous cell culture studies have identified intracellular signaling proteins that control proliferation and migration in response to extracellular cues from the wound microenvironment, confirming their importance in wound healing requires appropriate in vivo models. The Rho-family guanosine triphosphatase (GTPase) Rac1 is an effector of cellular responses to growth factors, cytokines, and adhesion proteins present in wounds, and it has long been suspected to be an important regulator of wound healing. Two different genetic models now confirm an essential role for Rac1 in wound healing and, further, identify a dual role for Rac1 in promoting keratinocyte migration and proliferation during wound re-epithelialization. This sets the stage for determining which of the known Rac1 pathways are critical for wound repair in vivo and for linking these pathways to specific integrin or growth factor receptors that mediate cellular responses to cues from the wound environment. Together with studies that implicate Rac1 in maintaining epidermal stem cell populations, these findings lay the foundation for identifying distinct epidermal compartments from which Rac1 controls different aspects of wound re-epithelialization.
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PMID:Double duty for Rac1 in epidermal wound healing. 1757 42

Differentiation of hepatic stellate cells (HSCs) to extracellular matrix- and growth factor-producing cells supports liver regeneration through promotion of hepatocyte proliferation. We show that the neurotrophin receptor p75(NTR), a tumor necrosis factor receptor superfamily member expressed in HSCs after fibrotic and cirrhotic liver injury in humans, is a regulator of liver repair. In mice, depletion of p75(NTR) exacerbated liver pathology and inhibited hepatocyte proliferation in vivo. p75 (NTR-/-) HSCs failed to differentiate to myofibroblasts and did not support hepatocyte proliferation. Moreover, inhibition of p75(NTR) signaling to the small guanosine triphosphatase Rho resulted in impaired HSC differentiation. Our results identify signaling from p75(NTR) to Rho as a mechanism for the regulation of HSC differentiation to regeneration-promoting cells that support hepatocyte proliferation in the diseased liver.
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PMID:The simple truth is seldom true and never simple: dual role for p75(NTR) in transdifferentation and cell death of hepatic stellate cells. 1739 31

Activation of G(i)-coupled receptors in neutrophils stimulates class IB phosphoinositide 3-kinase (PI3K) (also known as PI3Kgamma) through the combined actions of Gbetagamma subunits and the small guanosine triphosphatase (GTPase) Ras, resulting in the production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] in the plasma membrane. In most cases, the effectors of this pathway possess a pleckstrin homology (PH) domain that mediates the interaction with and regulation by these two lipid messengers. These direct effectors sit within a complex regulatory network that includes several other signaling pathways and that is responsible for the control of important neutrophil functions, including adhesion, chemotaxis, secretion, and the "respiratory burst" [activation of the nicotinamide adenosine diphosphate (NADPH) oxidase]. Although the molecular details that link the direct effectors of class IB PI3K to these complex cell responses are still largely unknown, these responses involve complex regulation of small GTPases of the Rac, Rho, and Arf families.
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PMID:PI3K class IB pathway in neutrophils. 1792 74

A fundamental feature of cell polarity in response to spatial cues is asymmetric amplification of molecules generated by positive feedback signaling. We report a positive feedback loop between the guanosine triphosphatase Cdc42, a central determinant in eukaryotic cell polarity, and H(+) efflux by Na-H(+) exchanger 1 (NHE1), which is necessary at the front of migrating cells for polarity and directional motility. In response to migratory cues, Cdc42 is not activated in fibroblasts expressing a mutant NHE1 that lacks H(+) efflux, and wild-type NHE1 is not activated in fibroblasts expressing mutationally inactive Cdc42-N17. H(+) efflux by NHE1 is not necessary for release of Cdc42-guanosine diphosphate (GDP) from Rho GDP dissociation inhibitor or for the membrane recruitment of Cdc42 but is required for GTP binding by Cdc42 catalyzed by a guanine nucleotide exchange factor (GEF). Data indicate that GEF binding to phosphotidylinositol 4,5-bisphosphate is pH dependent, suggesting a mechanism for how H(+) efflux by NHE1 promotes Cdc42 activity to generate a positive feedback signal necessary for polarity in migrating cells.
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PMID:Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells. 1798 18

The successive steps involved in cell migration include extension of the leading process, followed by translocation of the soma and retraction of the trailing process. These events require the coordinated activity of various intracellular signaling mechanisms. Recent evidence suggests that the intracellular distribution of calcium ions and of the Rho guanosine triphosphatase (RhoGTPase), RhoA, are important components of these mechanisms. During migration, the growth cone of the leading process senses guidance cues present in the extracellular environment. These cues, acting through appropriate receptors on the growth cone, induce changes in the concentration of calcium, both in the growth cone and in the soma. These changes in the distribution of calcium cause a redistribution of intracellular RhoA and the eventual translocation of the soma. The trailing process is retracted as the cell moves forward.
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PMID:The role of intracellular calcium and RhoA in neuronal migration. 1800 Feb 35

Prostate cancer invariably recurs after androgen deprivation therapy. Growth of this recurrent/androgen-independent form of prostate cancer may be due to increased androgen receptor (AR) transcriptional activity in the absence of androgen. This ligand-independent AR activation is promoted by some growth factors but the mechanism is not well understood. Vav3, a Rho guanosine triphosphatase guanine nucleotide exchange factor, which is activated by growth factors, is up-regulated in human prostate cancer. We show here that Vav3 levels increase during in vivo progression of prostate cancer to androgen independence. Vav3 strikingly enhanced growth factor activation of AR in the absence of androgen. Because Vav3 may be chronically activated in prostate cancer by growth factor receptors, we examined the effects of a constitutively active (Ca) form of Vav3 on AR transcriptional activity. Ca Vav3 caused nuclear localization and ligand-independent activation of AR via the Rho guanosine triphosphatase, Rac1. Ca Rac1 activation of AR occurred, in part, through MAPK/ERK signaling. Expression of active Rac1 conferred androgen-independent growth of prostate cancer cells in culture, soft agar, and mice. These findings suggest that Vav3/Rac 1 signaling is an important modulator of ligand-independent AR transcriptional activity in prostate cancer progression.
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PMID:Ligand-independent activation of androgen receptors by Rho GTPase signaling in prostate cancer. 1807 21


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