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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rho GTPases regulate a multitude of cellular processes from cytoskeletal reorganization to gene transcription and are negatively regulated by GTPase-activating proteins (GAPs). Cdc42 GTPase-activating protein (CdGAP) is a ubiquitously expressed GAP for Rac1 and Cdc42. In this study, we set out to identify CdGAP-binding partners and, using a yeast two-hybrid approach, glycogen synthase kinase 3alpha (GSK-3alpha) was identified as a partner for CdGAP. GSK-3 exists in two isoforms, alpha and beta, and is involved in regulating many cellular functions from insulin response to tumorigenesis. We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. We report that the mRNA and protein levels of CdGAP are increased upon serum stimulation and that GSK-3 activity is necessary for the up-regulation of the protein levels of CdGAP but not for the increase in mRNA. We conclude that GSK-3 is an important regulator of CdGAP and that regulation of CdGAP protein levels by serum presents a novel mechanism for cells to control Cdc42/Rac1 GTPase signaling pathways.
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PMID:Glycogen synthase kinase-3 phosphorylates CdGAP at a consensus ERK 1 regulatory site. 1715 47

Drugs of abuse induce alterations in cytoskeletal and cytoskeleton associated genes in several brain areas. We have previously shown that acute MDMA regulates the mRNA level of Rnd3, a Rho GTPase involved in actin cytoskeleton regulation, in mice striatum. In this study we investigated the effects of single administration of cocaine, another psychostimulant with a slightly different mechanism of action, on the mRNA levels of the three members of the Rnd genes family (Rnd1, Rnd2 and Rnd3). Mice were treated with either MDMA (9 mg/kg) or cocaine (20 mg/jg) and brain samples (i.e. hippocampus, striatum and prefrontal cortex) were processed for quantitative real-time PCR assay 1, 2, 4 and 6 h after the injections. The expression level of Rnd2 was differentially affected depending on the drug, brain area and time point after injection. Interestingly the two drugs up-regulate Rnd3 gene expression in the three structures tested with some differences in the timing. The effects of MDMA on Rnd3 appear earlier in the hippocampus as compared to cocaine, while it is the opposite in the prefrontal cortex. However, in the dorsal striatum, the two drugs induce an early and significant up-regulation of Rnd3 expression that is longer-lasting in the case of MDMA. In the case of cocaine contrarily to what was observed with MDMA, this modulation could not be blocked with the ERK activation inhibitor SL327 suggesting that the two drugs lead to the same effect on Rnd3 by two distinct pathways.
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PMID:Rnd family genes are differentially regulated by 3,4-methylenedioxymethamphetamine and cocaine acute treatment in mice brain. 1719 87

Neurofibromatosis 1 (NF1) is a common genetic disease that predisposes patients to peripheral nerve tumors and central nervous system (CNS) abnormalities including low-grade astrocytomas and cognitive disabilities. Using mice with glial fibrillary acidic protein (GFAP)-targeted Nf1 loss (Nf1(GFAP)CKO mice), we found that Nf1(-/-) astrocytes proliferate faster and are more invasive than wild-type astrocytes. In light of our previous finding that aberrant expression of the MET receptor tyrosine kinase contributes to the invasiveness of human NF1-associated malignant peripheral nerve sheath tumors, we sought to determine whether MET expression is aberrant in the brains of Nf1 mutant mice. We found that Nf1(-/-) astrocytes express slightly more MET than wild-type cells in vitro, but do not express elevated MET in situ. However, fiber tracts containing myelinated axons in the hippocampus, midbrain, cerebral cortex, and cerebellum express higher than normal levels of MET in older (> or =6 months) Nf1(GFAP)CKO mice. Both Nf1(GFAP)CKO and wild-type astrocytes induced MET expression in neurites of wild-type hippocampal neurons in vitro, suggesting that astrocyte-derived signals may induce MET in Nf1 mutant mice. Because the Nf1 gene product functions as a RAS GTPase, we examined MET expression in the brains of mice with GFAP-targeted constitutively active forms of RAS. MET was elevated in axonal fiber tracts in mice with active K-RAS but not H-RAS. Collectively, these data suggest that loss of Nf1 in either astrocytes or GFAP(+) neural progenitor cells results in increased axonal MET expression, which may contribute to the CNS abnormalities in children and adults with NF1.
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PMID:Mice with GFAP-targeted loss of neurofibromin demonstrate increased axonal MET expression with aging. 1734 23

Tubules are the building blocks of epithelial organs and form in response to cues derived from morphogens such as hepatocyte growth factor (HGF). Relatively little is known about signaling pathways that orchestrate the cellular behaviors that constitute tubule development. Here, using three-dimensional cell cultures of Madin-Darby canine kidney cells, we show that the ARF6 GTPase is a critical determinant of tubule initiation in response to HGF. ARF6 is transiently activated during tubulogenesis and perturbing the ARF6 GTP/GDP cycle by inducible expression of ARF6 mutants defective in GTP binding or hydrolysis, inhibits the development of mature tubules. Further, we show that activation of ARF6 is necessary and sufficient to initiate tubule extension. The effect of ARF6 on tubule initiation is two-fold. First, ARF6 regulates the subcellular distribution of the GTPase, Rac1, to tubule extensions. Second, ARF6-induced ERK activation regulates Rac1 activation during tubule initiation through the expression of the receptor for urokinase type plasminogen activator. Thus, we have identified a cellular apparatus downstream of ARF6 activation, which regulates membrane and cytoskeleton remodeling necessary for the early stages of tubule development.
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PMID:ARF6-dependent activation of ERK and Rac1 modulates epithelial tubule development. 1736 98

Ras-GTPase-activating proteins (Ras-GAPs) have been implicated both as suppressors of Ras and as effectors in regulating cellular activities. To study whether Ras-GAPs have roles in tumor cell survival or not, mRNA levels of ras-related genes were measured in v-Ki-ras-transformed (DT) and the parental NIH/3T3 cells, using real-time PCR. mRNA levels of p120-Gap, Gap1(m), and PIK3CA were increased in DT cells compared with NIH/3T3 cells. p120-Gap and PIK3CA genes were induced by addition of serum or epidermal growth factor to serum-starved DT cells. Three anti-cancer drugs, an ERK kinase (MEK) inhibitor PD98059, a topoisomerase II poison doxorubicin (adriamycin), and a histone deacetylase inhibitor trichostatin A, selectively blocked the overexpression of p120-Gap and Gap1(m) genes in DT cells. These drugs also caused reversion of DT cells to the adherent shape associated with growth arrest. Our results suggest that p120-Gap and Gap1(m) genes provide important biomarkers for cancer therapies.
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PMID:Up-regulation of ras-GAP genes is reversed by a MEK inhibitor and doxorubicin in v-Ki-ras-transformed NIH/3T3 fibroblasts. 1736 62

Regulator of G-protein signaling (RGS) proteins accelerate GTP hydrolysis by heterotrimeric G-protein alpha subunits and thus inhibit signaling by many G protein-coupled receptors. Several RGS proteins have a multidomain architecture that adds further complexity to their roles in cell signaling in addition to their GTPase-accelerating activity. RGS12 contains a tandem repeat of Ras-binding domains but, to date, the role of this protein in Ras-mediated signal transduction has not been reported. Here, we show that RGS12 associates with the nerve growth factor (NGF) receptor tyrosine kinase TrkA, activated H-Ras, B-Raf, and MEK2 and facilitates their coordinated signaling to prolonged ERK activation. RGS12 is required for NGF-mediated neurite outgrowth of PC12 cells, but not outgrowth stimulated by basic fibroblast growth factor. siRNA-mediated knockdown of RGS12 expression also inhibits NGF-induced axonal growth in dissociated cultures of primary dorsal root ganglia neurons. These data suggest that RGS12 may play a critical, and receptor-selective, role in coordinating Ras-dependent signals that are required for promoting and/or maintaining neuronal differentiation.
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PMID:Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation. 1738 Jan 22

The chimaerin family of Rac GTPase-activating proteins (GAPs) has been implicated in neural development and tumor progression, although the cellular mechanisms of their effects are poorly understood. To study their physiologic function, we used the Drosophila retina as a model system. Reduced expression of the fly chimaerin ortholog RhoGAP5a in the pupal eye led to an excess of interommatidial pigment cells, aberrant cell contacts, and an increase in activated ERK that localized specifically to the plasma membrane. Reducing RhoGAP5A levels suppressed the effects of disrupted EGF receptor signaling. Perturbation of Rac activity led to similar phenotypes, whereas coexpression of Rac and RhoGAP5A-dsRNAi resulted in the elimination of adherens junctions between interommatidial cells. Our results reveal a role for chimaerin in the regulation of ERK signaling and cell-cell adhesion and have implications for its participation in epithelial development and tumor progression.
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PMID:Chimaerin and Rac regulate cell number, adherens junctions, and ERK MAP kinase signaling in the Drosophila eye. 1743 81

The Rit GTPase is widely expressed in developing and adult nervous systems, and our previous data with pheochromocytoma cells implicate Rit signaling in NGF-induced neurite outgrowth. In this study, we investigated a role for Rit in neuronal morphogenesis. Expression of a dominant-negative (dn) Rit mutant in hippocampal neurons inhibited axonal growth but potentiated dendritic growth. Conversely, a constitutively active (ca) Rit mutant promoted axonal growth but inhibited dendritic growth. Dendritogenesis is regulated differently in sympathetic neurons versus hippocampal neurons in that sympathetic neurons require NGF and bone morphogenetic proteins (BMPs) to trigger dendritic growth. Despite these differences, dnRit potentiated and caRit blocked BMP7-induced dendritic growth in sympathetic neurons. Biochemical studies indicated that BMP7 treatments that caused dendritic growth also decreased Rit GTP loading. Additional studies demonstrate that caRit increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and pharmacological inhibition of MEK1 (mitogen-activated protein kinase/ERK 1) blocked the axon-promoting and dendrite-inhibiting effects of caRit. These observations suggest that Rit is a convergence point for multiple signaling pathways and it functions to promote axonal growth but inhibit dendritic growth via activation of ERK1/2. Modulation of the activational status of Rit may therefore represent a generalized mechanism across divergent neuronal cell types for regulating axonal versus dendritic growth modes.
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PMID:The novel GTPase Rit differentially regulates axonal and dendritic growth. 1746 85

Oncogenic activation loop KIT mutations are observed in acute myeloid leukemia (AML) and systemic mastocytosis (SM); however, unlike the KIT juxtamembrane mutants, the activation loop mutants are insensitive to imatinib mesylate. Furthermore, as prior studies primarily used heterologous cell lines, the molecular mechanism(s) underlying oncogenic KIT-induced transformation in primary cells is poorly understood. We demonstrate that expression of KITD814V in primary hematopoietic stem/progenitor cells (HSC/Ps) and mast cell progenitors (MCps) induces constitutive KIT autophosphorylation, supports ligand-independent hyperproliferation, and promotes promiscuous cooperation with multiple cytokines. Genetic disruption of p85 alpha, the regulatory subunit of class IA lipid kinase phosphoinositol-3-kinase (PI3K), but not of p85 beta, or genetic disruption of the hematopoietic cell-specific Rho GTPase, Rac2, normalizes KITD814V-induced ligand-independent hyperproliferation. Additionally, deficiency of p85 alpha or Rac2 corrects the promiscuous hyperproliferation observed in response to multiple cytokines in both KITD814V-expressing HSC/Ps and MCps. Treatment of KITD814V-expressing HSC/Ps with a Rac inhibitor (NC23766) or with rapamycin showed a dose-dependent suppression in ligand-independent growth. Taken together, our results identify p85 alpha and Rac2 as potential novel therapeutic targets for the treatment of KITD814V-bearing AML and SM.
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PMID:Genetic and pharmacologic evidence implicating the p85 alpha, but not p85 beta, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis. 1748 98

The endoplasmic reticulum (ER) is a contiguous network of interconnected membrane sheets and tubules. The ER is differentiated into distinct domains, including the peripheral ER and nuclear envelope. Inhibition of two ER proteins, Rtn4a and DP1/NogoA, was previously shown to inhibit the formation of ER tubules in vitro. We show that the formation of ER tubules in vitro also requires a Rab family GTPase. Characterization of the 29 Caenorhabditis elegans Rab GTPases reveals that depletion of RAB-5 phenocopies the defects in peripheral ER structure that result from depletion of RET-1 and YOP-1, the C. elegans homologues of Rtn4a and DP1/NogoA. Perturbation of endocytosis by other means did not affect ER structure; the role of RAB-5 in ER morphology is thus independent of its well-studied requirement for endocytosis. RAB-5 and YOP-1/RET-1 also control the kinetics of nuclear envelope disassembly, which suggests an important role for the morphology of the peripheral ER in this process.
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PMID:A role for Rab5 in structuring the endoplasmic reticulum. 1759 21


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