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11.
Characterization of Mayven, a Novel Actin-binding Protein
Predominantly Expressed in Brain 总被引:6,自引:0,他引:6
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Margaret Soltysik-Espanola Rick A. Rogers Shuxian Jiang Tae-Aug Kim Roger Gaedigk Robert A. White Hava Avraham Shalom Avraham 《Molecular biology of the cell》1999,10(7):2361-2375
The cytoskeleton plays an important role in neuronal morphogenesis. We have identified and characterized a novel actin-binding protein, termed Mayven, predominantly expressed in brain. Mayven contains a BTB (broad complex, tramtrack, bric-a-brac)/POZ (poxvirus, zinc finger) domain-like structure in the predicted N terminus and "kelch repeats" in the predicted C-terminal domain. Mayven shares 63% identity (77% similarity) with the Drosophila ring canal ("kelch") protein. Somatic cell-hybrid analysis indicated that the human Mayven gene is located on chromosome 4q21.2, whereas the murine homolog gene is located on chromosome 8. The BTB/POZ domain of Mayven can self-dimerize in vitro, which might be important for its interaction with other BTB/POZ-containing proteins. Confocal microscopic studies of endogenous Mayven protein revealed a highly dynamic localization pattern of the protein. In U373-MG astrocytoma/glioblastoma cells, Mayven colocalized with actin filaments in stress fibers and in patchy cortical actin-rich regions of the cell margins. In primary rat hippocampal neurons, Mayven is highly expressed in the cell body and in neurite processes. Binding assays and far Western blotting analysis demonstrated association of Mayven with actin. This association is mediated through the "kelch repeats" within the C terminus of Mayven. Depolarization of primary hippocampal neurons with KCl enhanced the association of Mayven with actin. This increased association resulted in dynamic changes in Mayven distribution from uniform to punctate localization along neuronal processes. These results suggest that Mayven functions as an actin-binding protein that may be translocated along axonal processes and might be involved in the dynamic organization of the actin cytoskeleton in brain cells. 相似文献
12.
Mahmoud?HuleihelEmail author Hava?Golan Mordechai?Hallak 《Reproductive biology and endocrinology : RB&E》2004,2(1):17
Intrauterine infection is considered as one of the major maternal insults during pregnancy. Intrauterine infection during
pregnancy could lead to brain damage of the developmental fetus and offspring. Effects on the fetal, newborn, and adult central
nervous system (CNS) may include signs of neurological problems, developmental abnormalities and delays, and intellectual
deficits. However, the mechanisms or pathophysiology that leads to permanent brain damage during development are complex and
not fully understood. This damage may affect morphogenic and behavioral phenotypes of the developed offspring, and that mice
brain damage could be mediated through a final common pathway, which includes over-stimulation of excitatory amino acid receptor,
over-production of vascularization/angiogenesis, pro-inflammatory cytokines, neurotrophic factors and apoptotic-inducing factors. 相似文献
13.
Few tyrosine phosphatases support, rather than inhibit, survival of tumor cells. We present genetic evidence that receptor-type protein-tyrosine phosphatase (RPTP)-epsilon performs such a function, as cells from mammary epithelial tumors induced by activated Neu in mice genetically lacking RPTPepsilon appeared morphologically less transformed and exhibited reduced proliferation. We show that at the molecular level, RPTPepsilon activates Src, a known collaborator of Neu in mammary tumorigenesis. Lack of RPTPepsilon reduced Src activity and altered Src phosphorylation in tumor cells; RPTPepsilon dephosphorylated and activated Src; and Src bound a substrate-trapping mutant of RPTPepsilon. The altered morphology of tumor cells lacking RPTPepsilon was corrected by exogenous Src and exogenous RPTPepsilon or RPTPalpha; exogenous activated Src corrected also the growth rate phenotype. Together, these results suggest that the altered morphology of RPTPepsilon-deficient tumor cells is caused by reduced Src activity, caused, in turn, by lack of RPTPepsilon. Unexpectedly, the phenotype of RPTPepsilon-deficient tumor cells occurs despite expression of the related RPTPalpha, indicating that endogenous RPTPalpha does not compensate for the absence of RPTPepsilon in this case. We conclude that RPTPepsilon is a physiological activator of Src in Neu-induced mammary tumors and suggest that pharmacological inhibition of phosphatases that activate Src may be useful to augment direct pharmacological inhibition of Src. 相似文献
14.
Avraham HK Lee TH Koh Y Kim TA Jiang S Sussman M Samarel AM Avraham S 《The Journal of biological chemistry》2003,278(38):36661-36668
Vascular endothelial growth factor (VEGF) plays a significant role in blood-brain barrier breakdown and angiogenesis after brain injury. VEGF-induced endothelial cell migration is a key step in the angiogenic response and is mediated by an accelerated rate of focal adhesion complex assembly and disassembly. In this study, we identified the signaling mechanisms by which VEGF regulates human brain microvascular endothelial cell (HBMEC) integrity and assembly of focal adhesions, complexes comprised of scaffolding and signaling proteins organized by adhesion to the extracellular matrix. We found that VEGF treatment of HBMECs plated on laminin or fibronectin stimulated cytoskeletal organization and increased focal adhesion sites. Pretreating cells with VEGF antibodies or with the specific inhibitor SU-1498, which inhibits Flk-1/KDR receptor phosphorylation, blocked the ability of VEGF to stimulate focal adhesion assembly. VEGF induced the coupling of focal adhesion kinase (FAK) to integrin alphavbeta5 and tyrosine phosphorylation of the cytoskeletal components paxillin and p130cas. Additionally, FAK and related adhesion focal tyrosine kinase (RAFTK)/Pyk2 kinases were tyrosine-phosphorylated by VEGF and found to be important for focal adhesion sites. Overexpression of wild type RAFTK/Pyk2 increased cell spreading and the migration of HBMECs, whereas overexpression of catalytically inactive mutant RAFTK/Pyk2 markedly suppressed HBMEC spreading ( approximately 70%), adhesion ( approximately 82%), and migration ( approximately 65%). Furthermore, blocking of FAK by the dominant-interfering mutant FRNK (FAK-related non-kinase) significantly inhibited HBMEC spreading and migration and also disrupted focal adhesions. Thus, these studies define a mechanism for the regulatory role of VEGF in focal adhesion complex assembly in HBMECs via activation of FAK and RAFTK/Pyk2. 相似文献
15.
Nakamura T Yamashita H Nagano Y Takahashi T Avraham S Avraham H Matsumoto M Nakamura S 《FEBS letters》2002,517(1-3):190-194
The hyperthermophilic archaeon Methanococcus jannaschii uses several non-canonical enzymes to catalyze conserved reactions in glycolysis and gluconeogenesis. A highly diverged gene from that organism has been proposed to function as a phosphoglycerate mutase. Like the canonical cofactor-independent phosphoglycerate mutase and other members of the binuclear metalloenzyme superfamily, this M. jannaschii protein has conserved nucleophilic serine and metal-binding residues. Yet the substrate-binding residues are not conserved. We show that the genes at M. jannaschii loci MJ0010 and MJ1612 encode thermostable enzymes with phosphoglycerate mutase activity. Phylogenetic analyses suggest that this gene family arose before the divergence of the archaeal lineage. 相似文献
16.
Despite over 100 years of study, the intestinal pathogen Vibrio cholerae still causes epidemic disease in areas of the world where there is poor sanitation. While cholera toxin and the toxin-coregulated pilus (TCP) are known to be essential for full virulence, the role that other factors play has remained ill-defined. Herein, we describe a large-scale signature-tagged mutagenesis (STM) screen utilizing 100 pools of 96 mutants each to identify factors involved in colonization of the infant mouse small intestine. A total of 164 mutants representing transposition events into 95 different open reading frames were shown to be recovered at greatly reduced numbers from the infant mouse model. Analysis of the sites of insertion revealed multiple independent mutations within the rfb gene cluster, needed for synthesis of lipopolysaccharide (LPS), and the tcp gene cluster, needed for synthesis of the TCP. More importantly, in addition to these previously known colonization factors, we identified many genes whose activity in colonization was not previously appreciated. These can be divided into a number of functional groups, which include production of factors involved in metabolic activities, regulation of cellular processes, transport, adaptation to stress and unknown functions. In addition, we describe the reiterative use of STM, whereby colonization-defective mutants were assembled into virulence-attenuated pools (VAPs), which were used to begin to reveal roles that the identified virulence factors play in the infection process. Nine new factors were shown to be crucial for the V. cholerae acid tolerance response, which has previously been hypothesized to be important for epidemic spread of cholera. Competition assays of these nine acid tolerance response (ATR)-defective mutants revealed that mutations in gshB, hepA and recO result in a 1000-fold reduction in colonization. 相似文献
17.
Kim S Zagozdzon R Meisler A Baleja JD Fu Y Avraham S Avraham H 《The Journal of biological chemistry》2002,277(39):36465-36470
Our previous studies demonstrated that Csk homologous kinase (CHK) acts as a negative growth regulator of human breast cancer through inhibition of ErbB-2/neu-mediated Src family kinase activity (Bougeret, C., Jiang, S., Keydar, I., and Avraham, H. (2001) J. Biol. Chem. 276, 33711-33720. The interaction between the CHK SH2 domain and Tyr(P)(1248) of the ErbB-2 receptor has been shown to be specific and critical for CHK function. In this report, we investigated whether the interaction of the CHK SH2 domain and ErbB-2 is directly related to the inhibition of heregulin-stimulated Src kinase activity. We constructed three CHK SH2 domain binding mutants: G129R (enhanced binding), R147K (inhibited binding), and R147A (disrupted binding). NMR spectra for the domains of each construct were used to evaluate their interaction with a Tyr(P)(1248)-containing ErbB-2 peptide. G129R showed enhanced binding to ErbB-2, whereas binding was completely disrupted by R147A. The enhanced binding mutant showed chemical shift changes at the same residues as wild-type CHK, indicating that this mutant has the same binding characteristics as the wild-type protein. Furthermore, inhibition of heregulin-stimulated Src kinase activity was markedly diminished by R147A, whereas G129R-mediated inhibition was stronger as compared with wild-type CHK. These results indicate that the specific interaction of CHK and ErbB-2 via the SH2 domain of CHK is directly related to the growth inhibitory effects of CHK. These new CHK high affinity binding constructs may serve as good candidates for inhibition of the ErbB-2/Src transduction pathway in gene therapy studies in breast cancer. 相似文献
18.
Activation of pyk2/related focal adhesion tyrosine kinase and focal adhesion kinase in cardiac remodeling 总被引:8,自引:0,他引:8
Melendez J Welch S Schaefer E Moravec CS Avraham S Avraham H Sussman MA 《The Journal of biological chemistry》2002,277(47):45203-45210
Cellular remodeling during progression of dilation involves focal adhesion contact reorganization. However, the signaling mechanisms and structural consequences leading to impaired cardiomyocyte adhesion are poorly defined. These events were studied in tropomodulin-overexpressing transgenic mice that develop dilated cardiomyopathy associated with chronic elevation of intracellular calcium. Analysis of tropomodulin-overexpressing transgenic hearts by immunoblot and confocal microscopy revealed activation and redistribution of signaling molecules known to regulate adhesion. Calcium-dependent pyk2/related focal adhesion tyrosine kinase (RAFTK) showed changes in expression and phosphorylation state, similar to changes observed for a related downstream target molecule of pyk2/RAFTK termed focal adhesion kinase. Paxillin, the target substrate molecule for focal adhesion kinase phosphorylation, was redistributed in tropomodulin-overexpressing transgenic hearts with enhanced paxillin phosphorylation and cleavage. Certain aspects of the in vivo signaling phenotype including increased paxillin phosphorylation could be recapitulated in vitro using neonatal rat cardiomyocytes infected with recombinant adenovirus to overexpress tropomodulin. In addition, increasing intracellular calcium levels with ionomycin induced pyk2/RAFTK phosphorylation, and adenovirally mediated expression of wild-type pyk2/RAFTK resulted in increased phospho-pyk2/RAFTK levels and concomitant paxillin phosphorylation. Collectively, these results delineate a cardiomyocyte signaling pathway associated with dilation that has potential relevance for cardiac remodeling, focal adhesion reorganization, and loss of contractility. 相似文献
19.
Martin Akerman Roy Noy Ron Wolchinsky Orit Izhaki Ester Schallmach Adva Kubi Naama Zabari Jacob Schachter Uri Alon Yael Mandel‐Gutfreund Michal J Besser Yoram Reiter 《Molecular systems biology》2009,5(1)
Heterogeneous cell populations form an interconnected network that determine their collective output. One example of such a heterogeneous immune population is tumor‐infiltrating lymphocytes (TILs), whose output can be measured in terms of its reactivity against tumors. While the degree of reactivity varies considerably between different TILs, ranging from null to a potent response, the underlying network that governs the reactivity is poorly understood. Here, we asked whether one can predict and even control this reactivity. To address this we measured the subpopulation compositions of 91 TILs surgically removed from 27 metastatic melanoma patients. Despite the large number of subpopulations compositions, we were able to computationally extract a simple set of subpopulation‐based rules that accurately predict the degree of reactivity. This raised the conjecture of whether one could control reactivity of TILs by manipulating their subpopulation composition. Remarkably, by rationally enriching and depleting selected subsets of subpopulations, we were able to restore anti‐tumor reactivity to nonreactive TILs. Altogether, this work describes a general framework for predicting and controlling the output of a cell mixture. 相似文献
20.
We quantify the ‘permanent’ socio-economic impacts of the Great Hanshin-Awaji (Kobe) earthquake in 1995 by employing a large-scale panel dataset of 1,719 cities, towns, and wards from Japan over three decades. In order to estimate the counterfactual—i.e., the Kobe economy without the earthquake—we use the synthetic control method. Three important empirical patterns emerge: First, the population size and especially the average income level in Kobe have been lower than the counterfactual level without the earthquake for over fifteen years, indicating a permanent negative effect of the earthquake. Such a negative impact can be found especially in the central areas which are closer to the epicenter. Second, the surrounding areas experienced some positive permanent impacts in spite of short-run negative effects of the earthquake. Much of this is associated with movement of people to East Kobe, and consequent movement of jobs to the metropolitan center of Osaka, that is located immediately to the East of Kobe. Third, the furthest areas in the vicinity of Kobe seem to have been insulated from the large direct and indirect impacts of the earthquake. 相似文献