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  • 1. Bazigou, Eleni
    et al.
    Apitz, Holger
    Johansson, Jana
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Lorén, Christina
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hirst, Elizabeth M A
    Chen, Pei-Ling
    Palmer, Ruth
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Salecker, Iris
    Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila.2007Inngår i: Cell, ISSN 0092-8674, Vol. 128, nr 5, 961-75 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anaplastic lymphoma kinase (Alk) has been proposed to regulate neuronal development based on its expression pattern in vertebrates and invertebrates; however, its function in vivo is unknown. We demonstrate that Alk and its ligand Jelly belly (Jeb) play a central role as an anterograde signaling pathway mediating neuronal circuit assembly in the Drosophila visual system. Alk is expressed and required in target neurons in the optic lobe, whereas Jeb is primarily generated by photoreceptor axons and functions in the eye to control target selection of R1-R6 axons in the lamina and R8 axons in the medulla. Impaired Jeb/Alk function affects layer-specific expression of three cell-adhesion molecules, Dumbfounded/Kirre, Roughest/IrreC, and Flamingo, in the medulla. Moreover, loss of flamingo in target neurons causes some R8-axon targeting errors observed in Jeb and Alk mosaic animals. Together, these findings suggest that Jeb/Alk signaling helps R-cell axons to shape their environment for target recognition.

  • 2.
    Borge-Renberg, Karin
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Communicate or die: signalling in Drosophila immunity2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In general the work behind this thesis has revolved around the interesting pattern recognition gene family PGRPs (peptidoglycan recognition proteins). In particular the transmembrane PGRP-LC and to investigate its multifaceted role in the immune response of the fruit fly. As a well characterized model organism living on, and surrounded by, a multitude of microorganisms, Drosophila melanogaster serves as a great tool to gain insights about innate immunity. The two pillars of Drosophila innate immunity are the humoral and the cellular defense. Together they are very potent and can vanquish many infections, but if one of these pillars is damaged, chances are that the defense will collapse and the organism will succumb to the infection.

    The initial step in any immune response is to become aware of the pathogen. To accomplish this, innate immunity relies on recognizing common molecular building blocks necessary each group of microorganisms. One such building block is the bacterial cell wall component peptidoglycan. PGRPs are a widely spread gene family, and proteins of this family can bind peptidoglycan. We describe that there are 13 PGRP genes in Drosophila, one these codes for PGRP-LC. As it sits in the cell membrane in any of its three different splice forms, PGRP-LC can bind peptidoglycan, dimerize, and subsequently activate the imd/relish signalling pathway, and thereby trigger a vast production of antimicrobial peptides. These short peptides are the firearms of the humoral response. We identified three new inducible antimicrobial peptide genes, Diptericin B, Attacin C and Attacin D. Analyses of their sequences shed light on the evolution and relationship of these antimicrobial peptides

    The antimicrobial peptides are potent weapons, but without a functional cellular response the animal is at loss. Animals lacking blood cells are gravely compromised. It is interesting to find that PGRP-LC is involved at this end of the immune response equation as well. We have found that PGRP-LC is able to activate blood cells and increase numbers of circulating cells, in a JNK (Jun N-terminal kinase) dependent manner. Intriguingly this activation is not dependent on Relish, the NF-kB transcription factor of the Imd/Relish pathway.

    PGRP-LC activation funnels into both Imd/Relish and the JNK pathways. When PGRP-LC is lost, it appears that some basal, or background, JNK activation is lost. These effects are very mild, however the animal appears to become more sensitive to additional perturbations in this signalling pathway. This was the starting point when we started to re-evaluate Dredd, the caspase responsible for cleaving and activating Relish. Dredd also contributes to the JNK signalling pathway.

  • 3.
    Borge-Renberg, Karin
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Williams, Michael, J
    Hultmark, Dan
    PGRP-LC activates blood cells through JNK, and not via relishManuskript (Annet vitenskapelig)
  • 4.
    Borge-Renberg, Karin
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Williams, Michael, J
    Wiklund, Magda-Lena
    Hultmark, Dan
    PGRP-LC and Dredd interact with JNK signalling in Drosophila development and immunityManuskript (Annet vitenskapelig)
  • 5. Brey, Paul T.
    et al.
    Hultmark, DanUmeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Molecular mechanisms of immune responses in insects.1998Collection/Antologi (Annet vitenskapelig)
  • 6.
    Byström, Roberth
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Aisenbrey, Christopher
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Borowik, Tomasz
    Bokvist, Marcus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lindström, Fredrick
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sani, Marc-Antoine
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Gröbner, Gerhard
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Disordered proteins: Biological membranes as two-dimensional aggregation matrices2008Inngår i: Cell Biochemistry and Biophysics, ISSN 1085-9195, E-ISSN 1559-0283, Vol. 52, nr 3, 175-189 s.Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Aberrant folded proteins and peptides are hallmarks of amyloidogenic diseases. However, the molecular processes that cause these proteins to adopt non-native structures in vivo and become cytotoxic are still largely unknown, despite intense efforts to establish a general molecular description of their behavior. Clearly, the fate of these proteins is ultimately linked to their immediate biochemical environment in vivo. In this review, we focus on the role of biological membranes, reactive interfaces that not only affect the conformational stability of amyloidogenic proteins, but also their aggregation rates and, probably, their toxicity. We first provide an overview of recent work, starting with findings regarding the amphiphatic amyloid-β protein (Aβ), which give evidence that membranes can directly promote aggregation, and that the effectiveness in this process can be related to the presence of specific neuronal ganglioside lipids. In addition, we discuss the implications of recent research (medin as an detailed example) regarding putative roles of membranes in the misfolding behavior of soluble, non-amphiphatic proteins, which are attracting increasing interest. The potential role of membranes in exerting the toxic action of misfolded proteins will also be highlighted in a molecular context. In this review, we discuss novel NMR-based approaches for exploring membrane–protein interactions, and findings obtained using them, which we use to develop a molecular concept to describe membrane-mediated protein misfolding as a quasi-two-dimensional process rather than a three-dimensional event in a biochemical environment. The aim of the review is to provide researchers with a general understanding of the involvement of membranes in folding/misfolding processes in vivo, which might be quite universal and important for future research concerning amyloidogenic and misfolding proteins, and possible ways to prevent their toxic actions.

  • 7. Choe, Kwang-Min
    et al.
    Werner, Thomas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Anderson, Kathryn V.
    Requirement of a peptidoglycan recognition protein (PGRP) in Relish activation and antimicrobial immune responses in Drosophila.2002Inngår i: Science, Vol. 296, nr 12 April 2002, 359-362 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 8. Drosophila 12 Genomes Consortium,
    et al.
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Evolution of genes and genomes on the Drosophila phylogeny.2007Inngår i: Nature, ISSN 1476-4687, Vol. 450, nr 7167, 203-18 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

  • 9.
    Ekengren, Sophia
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    A family of Turandot-related genes in the humoral stress response of Drosophila.2001Inngår i: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 284, nr 4, 998-1003 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Drosophila Turandot A (TotA) gene was recently shown to encode a stress-induced humoral factor which gives increased resistance to the lethal effects of high temperature. Here we show that TotA belongs to a family of eight Tot genes distributed at three different sites in the Drosophila genome. All Tot genes are induced under stressful conditions such as bacterial infection, heat shock, paraquat feeding or exposure to ultraviolet light, suggesting that all members of this family play a role in Drosophila stress tolerance. The induction of the Tot genes differs in important respects from the heat shock response, such as the strong but delayed response to bacterial infection seen for several of the genes.

  • 10.
    Ekengren, Sophia
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Drosophila cecropin as an antifungal agent.1999Inngår i: Insect Biochem Mol Biol, ISSN 0965-1748, Vol. 29, nr 11, 965-72 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effects of Drosophila and Hyalophora cecropins were tested against different fungi, both insect pathogens and fungi from the normal environment of Drosophila. The fungi were generally found to be as susceptible to the cecropins as most bacteria, the only exception being the insect pathogen Beauveria bassiana which is completely resistant. This is also the only fungus tested which is virulent to Drosophila, giving 100% lethality within 5 days after injection. Lethal concentrations of cecropins against other fungi tested ranged between 0.4 and 4 microM. Andropin is less fungicidal than the cecropins, and Drosophila cecropin A is somewhat more potent than cecropin B. Even dense cultures of Saccharomyces cerevisiae can be cleared by micromolar concentrations of cecropin, whereas Geotrichum candidum is unaffected by cecropin when tested in a dense culture.

  • 11.
    Ekengren, Sophia
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Tryselius, Ylva
    Dushay, Mitchell S
    Liu, Gang
    Steiner, Håkan
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    A humoral stress response in Drosophila.2001Inngår i: Curr Biol, ISSN 0960-9822, Vol. 11, nr 9, 714-8 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ability to react to unfavorable environmental changes is crucial for survival and reproduction, and several adaptive responses to stress have been conserved during evolution [1-3]. Specific immune and heat shock responses mediate the elimination of invading pathogens and of damaged proteins or cells [4-6]. Furthermore, MAP kinases and other signaling factors mediate cellular responses to a very broad range of environmental insults [7-9]. Here we describe a novel systemic response to stress in Drosophila. The Turandot A (TotA) gene encodes a humoral factor, which is secreted from the fat body and accumulates in the body fluids. TotA is strongly induced upon bacterial challenge, as well as by other types of stress such as high temperature, mechanical pressure, dehydration, UV irradiation, and oxidative agents. It is also upregulated during metamorphosis and at high age. Strikingly, flies that overexpress TotA show prolonged survival and retain normal activity at otherwise lethal temperatures. Although TotA is only induced by severe stress, it responds to a much wider range of stimuli than heat shock genes such as hsp70 or immune genes such as Cecropin A1.

  • 12.
    Eneqvist, Therese
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet).
    Olofsson, Anders
    Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Ando, Yukio
    Miyakawa, Taihei
    Katsuragi, Shoichi
    Jass, Jana
    Molekylärbiologi (Medicinska fakulteten).
    Lundgren, Erik
    Molekylärbiologi (Medicinska fakulteten).
    Sauer-Eriksson, Elisabeth
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet).
    Disulfide-bond formation in the transthyretin mutant Y114C prevents amyloid fibril formation in vivo and in vitro.2002Inngår i: Biochemistry, ISSN 0006-2960, Vol. 41, nr 44, 13143-51 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Y114C mutation in human transthyretin (TTR) is associated with a particular form of familial amyloidotic polyneuropathy. We show that vitreous aggregates ex vivo consist of either regular amyloid fibrils or disordered disulfide-linked precipitates that maintain the ability to bind Congo red. Furthermore, we demonstrate in vitro that the ATTR Y114C mutant exists in three forms: one unstable but nativelike tetrameric form, one highly aggregated form in which a network of disulfide bonds is formed, and one fibrillar form. The disulfide-linked aggregates and the fibrillar form of the mutant can be induced by heat induction under nonreduced and reduced conditions, respectively. Both forms are recognized by the amyloid specific antibody MAB(39-44). In a previous study, we have linked exposure of this epitope in TTR to a three-residue shift in beta-strand D. The X-ray crystallographic structure of reduced tetrameric ATTR Y114C shows a structure similar to that of the wild type but with a more buried position of Cys10 and with beta-mercaptoethanol associated with Cys114, verifying the strong tendency for this residue to form disulfide bonds. Combined with the ex vivo data, our in vitro findings suggest that ATTR Y114C can lead to disease either by forming regular unbranched amyloid fibrils or by forming disulfide-linked aggregates that maintain amyloid-like properties but are unable to form regular amyloid fibrils.

  • 13.
    Englund, Camilla
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Birve, Anna
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Falileeva, Ludmilla
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Grabbe, Caroline
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Palmer, Ruth
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Miple1 and miple2 encode a family of MK/PTN homologues in Drosophila melanogaster.2006Inngår i: Dev Genes Evol, ISSN 0949-944X, Vol. 216, nr 1, 10-8 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Midkine (MK) and Pleiotrophin (PTN) are small heparin-binding cytokines with closely related structures. To date, this family of proteins has been implicated in multiple processes, such as growth, survival, and migration of various cells, and has roles in neurogenesis and epithelial-mesenchymal interaction during organogenesis. In this report, we have characterized two members of the MK/PTN family of proteins in Drosophila, named Miple1 and Miple2, from Midkine and Pleiotrophin. Drosophila miple1 and miple2 encode secreted proteins which are expressed in spatially restricted, nonoverlapping patterns during embryogenesis. Expression of miple1 can be found at high levels in the central nervous system, while miple2 is strongly expressed in the developing midgut endoderm. The identification of homologues of the MK/PTN family in this genetically tractable model organism should allow an analysis of their function during complex developmental processes.

  • 14. Englund, Camilla
    et al.
    Loren, Christina
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Grabbe, Caroline
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Varshney, Gaurav
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Deleuil, Fabiene
    Hallberg, Bengt
    Palmer, Ruth
    Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion2003Inngår i: Nature, ISSN 0028-0836, Vol. 425, nr 6957, 512-516 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 15. Evans, J D
    et al.
    Aronstein, K
    Chen, Y P
    Hetru, C
    Imler, J-L
    Jiang, H
    Kanost, M
    Thompson, G J
    Zou, Z
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Immune pathways and defence mechanisms in honey bees Apis mellifera.2006Inngår i: Insect Mol Biol, ISSN 0962-1075, Vol. 15, nr 5, 645-56 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Social insects are able to mount both group-level and individual defences against pathogens. Here we focus on individual defences, by presenting a genome-wide analysis of immunity in a social insect, the honey bee Apis mellifera. We present honey bee models for each of four signalling pathways associated with immunity, identifying plausible orthologues for nearly all predicted pathway members. When compared to the sequenced Drosophila and Anopheles genomes, honey bees possess roughly one-third as many genes in 17 gene families implicated in insect immunity. We suggest that an implied reduction in immune flexibility in bees reflects either the strength of social barriers to disease, or a tendency for bees to be attacked by a limited set of highly coevolved pathogens.

  • 16.
    Friberg, Josefin
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    The control of growth and metabolism in Caenorhabditis elegans2006Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The control of growth is a poorly understood aspect of animal development. This thesis focuses on body size regulation in Caenorhabditis elegans, and in particular, how worms grow to a certain size.

    In C. elegans, a key regulator of size is the TGFβ homologue DBL-1. Mutations that deplete the worm of DBL-1 result in a small body size, whereas overexpression of the gene renders long animals. The small mutants have the same number of cells as wild type suggesting that some or all cells are smaller. DBL-1 activates a TGFβ receptor leading to the nuclear localization of three Smad proteins which then initiate a transcriptional program for size control whose targets are mainly unknown. In order to learn more about how body size in C. elegans is regulated, we set up EMS mutagenesis screens to identify new loci that caused a long phenotype. A subset of the genes we have identified might function in the TGFβ signaling pathway regulating growth while others likely function in parallel pathways.

    One gene that we found in this screen, lon-3, encodes a cuticle collagen that genetically lies downstream of the DBL-1 TGFβ signaling pathway. Interestingly, loss of function mutations in lon-3 result in a Lon phenotype, whereas increasing the amount of LON-3 protein cause the worms to be dumpy, i.e. shorter, but slightly fatter than wild type. LON-3 is expressed in the hypodermis, the tissue from which the cuticle is synthesized and in which TGFβ signaling, regulating body size, has its focus. This study and previous work have shown that DBL-1 may affect body volume via effects on hypodermal nuclear ploidy, however this is unaffected in lon-3 mutants. Consistent with this finding, the volume of lon-3 mutant worms is not different from wild type. Taken together, our results suggest that another mechanism, by which TGFβ signaling can regulate body length, is by altering the shape of the cuticle via its effect on lon-3 and possibly other cuticle collagens.

    Studies in worms, flies and mice show that body size and nutrient allocation are closely connected. p70 S6-kinase (S6K) is a known regulator of cell and body size that also plays a role in metabolism. In mice and flies S6K mutants are much smaller than wild type. Our work on the worm homolog, rsks-1, shows that in worms as well, this gene is important for growth regulation and cell size. However, this effect seems to be at least in part independent of DBL-1 TGFβ signaling. Furthermore, rsks-1mutants have a 50 % increase in the amount of stored fat. Fatty acid metabolism has been shown to play an important role in environmental adaptation, especially in regards to temperature changes. Consistent with this idea, rsks-1 mutants appear to have difficulties in adjusting to such changes, reflected in a much-decreased fecundity at 15 and 25 °C compared to their cultivation temperature (20 °C).

    Within the nervous system the gene is specifically expressed in a subset of the chemosensory neurons that, when nutrients are abundant, secrete signals that promote growth. Intriguingly, this expression seems to be negatively regulated by insulin- like signaling, in contrast to the positive regulation of S6K by insulin in Drosophila and mice. Taken together we show that rsks-1 is an important regulator of growth and fat metabolism in Caenorhabditis elegans.

  • 17. Furuta, T
    et al.
    Tuck, S
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Kirchner, J
    Koch, B
    Auty, R
    Kitagawa, R
    Rose, A M
    Greenstein, D
    EMB-30: an APC4 homologue required for metaphase-to-anaphase transitions during meiosis and mitosis in Caenorhabditis elegans.2000Inngår i: Mol Biol Cell, ISSN 1059-1524, Vol. 11, nr 4, 1401-19 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 18. Ge, Changrong
    et al.
    Georgiev, Alexander
    Öhman, Anders
    Wieslander, Åke
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Kelly, Amelie A.
    Tryptophan Residues Promote Membrane Association for a Plant Lipid Glycosyltransferase Involved in Phosphate Stress2011Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, nr 8, 6669-6684 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chloroplast membranes contain a substantial excess of the nonbilayer-prone monogalactosyldiacylglycerol (GalDAG) over the biosynthetically consecutive, bilayer-forming digalactosyldiacylglycerol (GalGalDAG), yielding a high membrane curvature stress. During phosphate shortage, plants replace phospholipids with GalGalDAG to rescue phosphate while maintaining membrane homeostasis. Here we investigate how the activity of the corresponding glycosyltransferase (GT) in Arabidopsis thaliana (atDGD2) depends on local bilayer properties by analyzing structural and activity features of recombinant protein. Fold recognition and sequence analyses revealed a two-domain GT-B monotopic structure, present in other plant and bacterial glycolipid GTs, such as the major chloroplast GalGalDAG GT atDGD1. Modeling led to the identification of catalytically important residues in the active site of atDGD2 by site-directed mutagenesis. The DGD synthases share unique bilayer interface segments containing conserved tryptophan residues that are crucial for activity and for membrane association. More detailed localization studies and liposome binding analyses indicate differentiated anchor and substrate-binding functions for these separated enzyme interface regions. Anionic phospholipids, but not curvature-increasing nonbilayer lipids, strongly stimulate enzyme activity. From our studies, we propose a model for bilayer "control" of enzyme activity, where two tryptophan segments act as interface anchor points to keep the substrate region close to the membrane surface. Binding of the acceptor substrate is achieved by interaction of positive charges in a surface cluster of lysines, arginines, and histidines with the surrounding anionic phospholipids. The diminishing phospholipid fraction during phosphate shortage stress will then set the new GalGalDAG/phospholipid balance by decreasing stimulation of atDGD2.

  • 19.
    Grabbe, Caroline
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Protein tyrosine kinases and the regulation of signalling and adhesion in drosophila melanogaster2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In order to build a multi-cellular organism and to regulate cellular functions, cells need to communicate with each other, as well as tightly regulate their behaviour in response to environmental changes. For these purposes all eukaryotic cells express a large number of membrane spanning receptors that either themselves contain catalytic activity or via cytoplasmic effector enzymes, function to transmit “signals” from the cell exterior to induce appropriate responses within the cell. Protein tyrosine kinases (PTKs) are important signalling molecules, represented by the transmembrane receptor tyrosine kinases (RTKs) in addition to the cytoplasmic non-receptor PTKs, which alter cell behaviour by phosphorylating target proteins. An additional requirement for proper signalling and multicellular organisation is the adhesion between cells as well as adhesion of cells to the extracellular matrix (ECM).

    Adhesion between cells and the ECM is mainly mediated by the integrin family of cell surface receptors, which functions as a structural link between the ECM and the actin cytoskeleton as well as important centres for signalling. Mammalian studies have implicated the cytoplasmic Focal Adhesion Kinase (FAK), as a major transmitter of signalling emanating from integrins, regulating cell migration, survival, proliferation and differentiation. In our studies of the sole FAK family member in Drosophila, Fak56, we have concluded that the deletion of Fak56 from the fruit fly genome causes no obvious defects in integrin-mediated adhesion, migration or signalling in vivo. Consequently, in contrast to the embryonic lethality observed in mouse knockouts, Fak56 mutant flies are both viable and fertile. However, we do find a clear genetic interaction between Fak56 and Drosophila integrins. Additionally, overexpression studies indeed indicate Fak56 as a negative regulator of integrin adhesion, given that excess Fak56 protein phenocopies loss of integrin function, causing phenotypes such as muscle detachment and wing blistering.

    In Drosophila, as well as in mammals, FAK family proteins are highly abundant in the CNS and in our studies we have identified a requirement of Fak56 in synaptic transmission at neuromuscular junctions. Lack of Fak56 causes a weakening of action potential conduction, resulting in sensitivity to high-frequency mechanical and electrical stimulation, manifested by epileptic-like seizures and paralysis in Fak56 mutants, a phenotype known as Bang Sensitivity (BS) in flies. We also show that Fak56 phosphorylation is directly modulated in response to alterations in intracellular calcium levels, supporting a role for Fak56 in neurotransmission.

    Fak56 is directly activated by the Drosophila Anaplastic Lymphoma Kinase, DAlk, receptor which was identified in our lab. We characterised DAlk as a novel RTK that is expressed in the embryonic CNS and mesoderm where it drives activation of the ERK/MAPK pathway. Indeed, we found DAlk to ectopically induce protein tyrosine phosphorylation and specifically phosphorylation of ERK, resulting in autonomous cell transformation and uncontrolled tissue growth. Subsequently, we identified a requirement for DAlk function during Drosophila embryogenesis, where it displays an essential role in gut development. Specifically, we identified the secreted molecule Jelly belly (Jeb) as a ligand for DAlk and showed that Jeb-DAlk interaction activates an ERK-mediated signalling pathway essential for visceral muscle specification and fusion, and consequently formation of the gut.

    The potent ability of PTKs to regulate cell behaviour, together with the strong linkage between RTK dysregulation and tumour formation, renders the negative regulation of kinase activity an important area of research. We have identified the Drosophila homologue of Cbl-interacting protein of 85kDa, dCIN85, an adaptor molecule which in mammalian cells has shown involvement in RTK endocytosis and downregulation, as well as in the regulation of actin cytoskeleton dynamics. In the fruit fly, dCIN85 displays essential functions, given that dCIN85 loss of function mutants display a grand-child less phenotype. Generation of a dCIN85 antibody, together with isoform-specific transgenic flies, have allowed us to observe a punctuate localization pattern of the SH3-domain containing dCIN85 variants, representing Rab5-positive endosomal structures. This, in addition to the confirmation of a direct dCIN85-dCbl interaction, indicates an evolutionary conservation of dCIN85 function. Interestingly, dCIN85 co-localises with dRICH1, a Cdc42 specific RhoGAP, in differentiated photoreceptor cells in eye imaginal discs. This may imply a role for dCIN85 in the regulation of the specialised endocytic recycling processes required for the assembly/maintenance of tight junctions and establishment of cell polarity in epithelial tissues.

  • 20.
    Grabbe, Caroline
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Haglund, Kaisa
    Eriksson, Therese
    Varshney, Gaurav
    Aspenström, Pontus
    Dikic, Ivan
    Palmer, Ruth
    The Drosophila homologue of the endocytic regulator CIN85 interacts with the RhoGAP RICH1Manuskript (Annet vitenskapelig)
  • 21.
    Grabbe, Caroline
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Ueda, Atsushi
    Lee, Jisue
    Wu, Chun-Fang
    Palmer, Ruth
    Mutation of Drosophila focal adhesion kinase induces bang sensitive behaviour and disrupts axonal conduction and synaptic transmissionManuskript (Annet vitenskapelig)
  • 22.
    Grabbe, Caroline
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Zervas, Christos G
    Hunter, Tony
    Brown, Nicholas H
    Palmer, Ruth
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Focal adhesion kinase is not required for integrin function or viability in Drosophila.2004Inngår i: Development, ISSN 0950-1991, Vol. 131, nr 23, 5795-5805 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mammalian focal adhesion kinase (FAK) family of non-receptor protein-tyrosine kinases has been implicated in controlling a multitude of cellular responses to the engagement of cell-surface integrins and G-protein-coupled receptors. The high level of sequence conservation between the mammalian proteins and the Drosophila homologue of FAK, Fak56, suggested that it would have similar functions. However, we show here that Drosophila Fak56 is not essential for integrin functions in adhesion, migration or signaling in vivo. Furthermore, animals lacking Fak56 are viable and fertile, demonstrating that Fak56 is not essential for other developmental or physiological functions. Despite this, overexpressed Fak56 is a potent inhibitor of integrins binding to the extracellular matrix, suggesting that Fak56 may play a subtle role in the negative regulation of integrin adhesion.

  • 23.
    Habayeb, Mazen
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Ekengren, Sophia
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Nora virus, a persistent virus in Drosophila, defines a new picorna-like virus family.2006Inngår i: Journal of General Virology, ISSN 0022-1317, Vol. 87, nr Pt 10, 3045-3051 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several viruses, including picornaviruses, are known to establish persistent infections, but the mechanisms involved are poorly understood. Here, a novel picorna-like virus, Nora virus, which causes a persistent infection in Drosophila melanogaster, is described. It has a single-stranded, positive-sense genomic RNA of 11879 nt, followed by a poly(A) tail. Unlike other picorna-like viruses, the genome has four open reading frames (ORFs). One ORF encodes a picornavirus-like cassette of proteins for virus replication, including an iflavirus-like RNA-dependent RNA polymerase and a helicase that is related to those of mammalian picornaviruses. The three other ORFs are not closely related to any previously described viral sequences. The unusual sequence and genome organization in Nora virus suggest that it belongs to a new family of picorna-like viruses. Surprisingly, Nora virus could be detected in all tested D. melanogaster laboratory stocks, as well as in wild-caught material. The viral titres varied enormously, between 10(4) and 10(10) viral genomes per fly in different stocks, without causing obvious pathological effects. The virus was also found in Drosophila simulans, a close relative of D. melanogaster, but not in more distantly related Drosophila species. It will now be possible to use Drosophila genetics to study the factors that control this persistent infection.

  • 24. Habermeyer, Michael
    et al.
    Fritz, Jessica
    Barthelmes, Hans U
    Christensen, Morten O
    Larsen, Morten K
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Boege, Fritz
    Marko, Doris
    Anthocyanidins modulate the activity of human DNA topoisomerases I and II and affect cellular DNA integrity.2005Inngår i: Chemical Research in Toxicology, ISSN 0893-228X, Vol. 18, nr 9, 1395-404 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the present study, we investigated the effect of anthocyanidins on human topoisomerases I and II and its relevance for DNA integrity within human cells. Anthocyanidins bearing vicinal hydroxy groups at the B-ring (delphinidin, DEL; cyanidin, CY) were found to potently inhibit the catalytic activity of human topoisomerases I and II, without discriminating between the IIalpha and the IIbeta isoforms. However, in contrast to topoisomerase poisons, DEL and CY did not stabilize the covalent DNA-topoisomerase intermediates (cleavable complex) of topoisomerase I or II. Using recombinant topoisomerase I, the presence of CY or DEL (> or = 1 microM) effectively prohibited the stabilization of the cleavable complex by the topoisomerase I poison camptothecin. We furthermore investigated whether the potential protective effect vs topoisomerase I poisons is reflected also on the cellular level, affecting the DNA damaging properties of camptothecin. Indeed, in HT29 cells, low micromolar concentrations of DEL (1-10 microM) significantly diminished the DNA strand breaking effect of camptothecin (100 microM). However, at concentrations > or = 50 microM, all anthocyanidins tested (delphinidin, cyanidin, malvidin, pelargonidin, and paeonidin), including those not interfering with topoisomerases, were found to induce DNA strand breaks in the comet assay. All of these analogues were able to compete with ethidium bromide for the intercalation into calf thymus DNA and to replace the minor groove binder Hoechst 33258. These data indicate substantial affinity to double-stranded DNA, which might contribute at least to the DNA strand breaking effect of anthocyanidins at higher concentrations (> or = 50 microM).

  • 25. Hallgren, Jenny
    et al.
    Bäckström, Stefan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Estrada, Sergio
    Thuveson, Maria
    Pejler, Gunnar
    Histidines are critical for heparin-dependent activation of mast cell tryptase.2004Inngår i: Journal of Immunology, ISSN 0022-1767, Vol. 173, nr 3, 1868-75 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mast cell tryptase is a tetrameric serine protease that is stored in complex with negatively charged heparin proteoglycans in the secretory granule. Tryptase has potent proinflammatory properties and has been implicated in diverse pathological conditions such as asthma and fibrosis. Previous studies have shown that tryptase binds tightly to heparin, and that heparin is required in the assembly of the tryptase tetramer as well as for stabilization of the active tetramer. Because the interaction of tryptase with heparin is optimal at acidic pH, we investigated in this study whether His residues are of importance for the heparin binding, tetramerization, and activation of the tryptase mouse mast cell protease 6. Molecular modeling of mouse mast cell protease 6 identified four His residues, H35, H106, H108, and H238, that are conserved among pH-dependent tryptases and are exposed on the molecular surface, and these four His residues were mutated to Ala. In addition, combinations of different mutations were prepared. Generally, the single His-Ala mutations did not cause any major defects in heparin binding, activation, or tetramerization, although some effect of the H106A mutation was observed. However, when several mutations were combined, large defects in all of these parameters were observed. Of the mutants, the triple mutant H106A/H108A/H238A was the most affected with an almost complete inability to bind to heparin and to form active tryptase tetramers. Taken together, this study shows that surface-exposed histidines mediate the interaction of mast cell tryptase with heparin and are of critical importance in the formation of active tryptase tetramers.

  • 26.
    Hedengren, Marika
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Borge, Karin
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Expression and evolution of the Drosophila attacin/diptericin gene family.2000Inngår i: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 279, nr 2, 574-81 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe the genes for three new glycine-rich antimicrobial peptides in Drosophila, two attacins (AttC and AttD) and one diptericin (DptB). Their structures support the proposal that these glycine-rich antimicrobial peptides evolved from a common ancestor and are probably also related to proline-rich peptides such as drosocin. AttC is similar to the nearby AttA and AttB genes. AttD is more divergent and located on a different chromosome. Intriguingly, AttD may encode an intracellular attacin. DptB is linked in tandem to the closely related Diptericin. However, the DptB gene product contains a furin-like cleavage site and may be processed in an attacin-like fashion. All attacin and diptericin genes are induced after bacterial challenge. This induction is reduced in imd mutants, and unexpectedly also in Tl(-) mutants. The 18w mutation particularly affects the induction of AttC, which may be a useful marker for 18w signaling.

  • 27.
    Hedengren, Marika
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Åsling, Bengt
    Dushay, Mitchell S
    Ando, Istvan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Ekengren, Sophia
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Wihlborg, Margareta
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Relish, a central factor in the control of humoral but not cellular immunity in Drosophila.1999Inngår i: Mol Cell, ISSN 1097-2765, Vol. 4, nr 5, 827-37 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The NF-kappa B-like Relish gene is complex, with four transcripts that are all located within an intron of the Nmdmc gene. Using deletion mutants, we show that Relish is specifically required for the induction of the humoral immune response, including both antibacterial and antifungal peptides. As a result, the Relish mutants are very sensitive to infection. A single cell of E. cloacae is sufficient to kill a mutant fly, and the mutants show increased susceptibility to fungal infection. In contrast, the blood cell population, the hematopoietic organs, and the phagocytic, encapsulation, and melanization responses are normal. Our results illustrate the importance of the humoral response in Drosophila immunity and demonstrate that Relish plays a key role in this response.

  • 28.
    Hedengren-Olcott, Marika
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Olcott, Michael C
    Mooney, Duane T
    Ekengren, Sophia
    Geller, Bruce L
    Taylor, Barbara J
    Differential activation of the NF-kappaB-like factors Relish and Dif in Drosophila melanogaster by fungi and Gram-positive bacteria.2004Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 279, nr 20, 21121-7 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The current model of immune activation in Drosophila melanogaster suggests that fungi and Gram-positive (G(+)) bacteria activate the Toll/Dif pathway and that Gram-negative (G(-)) bacteria activate the Imd/Relish pathway. To test this model, we examined the response of Relish and Dif (Dorsal-related immunity factor) mutants to challenge by various fungi and G(+) and G(-) bacteria. In Relish mutants, the Cecropin A gene was induced by the G(+) bacteria Micrococcus luteus and Staphylococcus aureus, but not by other G(+) or G(-) bacteria. This Relish-independent Cecropin A induction was blocked in Dif/Relish double mutant flies. Induction of the Cecropin A1 gene by M. luteus required Relish, whereas induction of the Cecropin A2 gene required Dif. Intact peptidoglycan (PG) was necessary for this differential induction of Cecropin A. PG extracted from M. luteus induced Cecropin A in Relish mutants, whereas PGs from the G(+) bacteria Bacillus megaterium and Bacillus subtilis did not, suggesting that the Drosophila immune system can distinguish PGs from various G(+) bacteria. Various fungi stimulated antimicrobial peptides through at least two different pathways requiring Relish and/or Dif. Induction of Attacin A by Geotrichum candidum required Relish, whereas activation by Beauvaria bassiana required Dif, suggesting that the Drosophila immune system can distinguish between at least these two fungi. We conclude that the Drosophila immune system is more complex than the current model. We propose a new model to account for this immune system complexity, incorporating distinct pattern recognition receptors of the Drosophila immune system, which can distinguish between various fungi and G(+) bacteria, thereby leading to selective induction of antimicrobial peptides via differential activation of Relish and Dif.

  • 29. Honeybee Genome Sequencing Consortium, the
    et al.
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Insights into social insects from the genome of the honeybee Apis mellifera.2006Inngår i: Nature, ISSN 1476-4687, Vol. 443, nr 7114, 931-49 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Here we report the genome sequence of the honeybee Apis mellifera, a key model for social behaviour and essential to global ecology through pollination. Compared with other sequenced insect genomes, the A. mellifera genome has high A+T and CpG contents, lacks major transposon families, evolves more slowly, and is more similar to vertebrates for circadian rhythm, RNA interference and DNA methylation genes, among others. Furthermore, A. mellifera has fewer genes for innate immunity, detoxification enzymes, cuticle-forming proteins and gustatory receptors, more genes for odorant receptors, and novel genes for nectar and pollen utilization, consistent with its ecology and social organization. Compared to Drosophila, genes in early developmental pathways differ in Apis, whereas similarities exist for functions that differ markedly, such as sex determination, brain function and behaviour. Population genetics suggests a novel African origin for the species A. mellifera and insights into whether Africanized bees spread throughout the New World via hybridization or displacement.

  • 30.
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Drosophila immunity: paths and patterns.2003Inngår i: Curr Opin Immunol, ISSN 0952-7915, Vol. 15, nr 1, 12-9 s.Artikkel, forskningsoversikt (Annet (populærvitenskap, debatt, mm))
    Abstract [en]

    Flies respond to infection with both humoral and cellular immune defenses, including a powerful set of inducible peptide antibiotics as well as actively proliferating and differentiating blood cells. The system that activates these responses is related to that of the innate immune defense in humans. A key role in Drosophila immunity is played by the recently discovered peptidoglycan recognition proteins. These pattern recognition molecules relay signals via two main signaling pathways. The imd/Relish pathway is responsible for the main part of the humoral response. The Toll/Dif pathway activates the blood cells and induces the antifungal peptide Drosomycin.

  • 31.
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Model organism immunology: What flies can tell us about immunity2000Inngår i: J. Leukoc. Biol., Vol. 57, nr Suppl S, 19-19 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 32.
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Quantification of antimicrobial activity, using the inhibition-zone assay1998Inngår i: Techniques in insect immunology, SOS Publications, Fair Haven , 1998, 103-107 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    One of the most popular antimicrobial assays is based on the simple principle that the sample is applied on a bacterial plate, seeded with bacteria or fungi. The effect is recorded as a zone of inhibited bacterial growth. This assay will here be referred to as the inhibition-zone assay.

  • 33.
    Hultmark, Dan
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Borge Renberg, Karin
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Drosophila immunity: is antigen processing the first step?2007Inngår i: Curr Biol, ISSN 0960-9822, Vol. 17, nr 1, R22-4 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A new genetic study has shown that the phagocytic ability of Drosophila blood cells, the hemocytes, may be important for the further induction of an antibacterial response in other tissues.

  • 34.
    Hultmark, Dan
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Ekengren, Sophia
    A cytokine in the Drosophila stress response.2003Inngår i: Dev Cell, ISSN 1534-5807, Vol. 5, nr 3, 360-1 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The fruit fly, Drosophila melanogaster, has become a popular tool for studying immediate reactions to environmental hazards, such as the heat shock and innate immune responses. In mammals, protective responses to infections and other insults are coordinated by a complex network of cytokines that mediate cell-to-cell signaling. By contrast, the corresponding heat shock and innate immune responses in Drosophila have usually been regarded as cell-autonomous processes. However, in this issue of Developmental Cell, show that cytokines do play a role in mediating an acute phase response in this organism.

  • 35.
    Hörnberg, Andreas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet).
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Eneqvist, Therese
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet).
    Lundgren, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Sauer-Eriksson, Elisabeth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet).
    The β-strand D of transthyretin trapped in two discrete conformations2004Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1700, nr 1, 93-104 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Conformational changes in native and variant forms of the human plasma protein transthyretin (TTR) induce several types of amyloid diseases. Biochemical and structural studies have mapped the initiation site of amyloid formation onto residues at the outer C and D beta-strands and their connecting loop. In this study, we characterise an engineered variant of transthyretin, Ala108Tyr/Leu110Glu, which is kinetically and thermodynamically more stable than wild-type transthyretin, and as a consequence less amyloidogenic. Crystal structures of the mutant were determined in two space groups, P2(1)2(1)2 and C2, from crystals grown in the same crystallisation set-up. The structures are identical with the exception for residues Leu55-Leu58, situated at beta-strand D and the following DE loop. In particular, residues Leu55-His56 display large shifts in the C2 structure. There the direct hydrogen bonding between beta-strands D and A has been disrupted and is absent, whereas the beta-strand D is present in the P2(1)2(1)2 structure. This difference shows that from a mixture of metastable TTR molecules, only the molecules with an intact beta-strand D are selected for crystal growth in space group P2(1)2(1)2. The packing of TTR molecules in the C2 crystal form and in the previously determined amyloid TTR (ATTR) Leu55Pro crystal structure is close-to-identical. This packing arrangement is therefore not unique in amyloidogenic mutants of TTR.

  • 36. István, Andó
    et al.
    Barbara, Laurinyecz
    István, Nagy
    Róbert, Márkus
    Rus, Florentina
    Balázs, Váczi
    Lános, Zsámboki
    László, Fehér
    Gateff, Elisabeth
    Hultmark, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Kurucz, Éva
    Our archaic heritage: the innate immunity. The cellular immunity of Drosophila [Ösi örökségünk: a veleszületett immunitás. A Drosophila sejtes immunitása]2003Inngår i: Magyar Immunológia, Vol. 2, nr 4, 39-45 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Authors describe the essentials of the cellular immunity of Drosophila. They describe the Drosophila CD system, the main blood cell lineages and a blood cell differentiation model based on the expression of the CD antigens.

  • 37.
    Kao, Gautam
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten). Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Kirurgi.
    Nordenson, Cecilia
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Kirurgi.
    Still, Maria
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap.
    Rönnlund, Agneta
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Tuck, Simon
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Naredi, Peter
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Kirurgi.
    ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells.2007Inngår i: Cell, ISSN 0092-8674, Vol. 128, nr 3, 577-87 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 38.
    Kao, Gautam
    et al.
    Department of Genetics, University of Pennsylvania, Philadelphia, USA.
    Tuck, Simon
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Baillie, David
    Department of Biological Sciences, Simon Fraser University, Canada.
    Sundaram, Meera V.
    Department of Genetics, University of Pennsylvania, Philadelphia, USA.
    C. elegans SUR-6/PR55 cooperates with LET-92/protein phosphatase 2A and promotes Raf activity independently of inhibitory Akt phosphorylation sites2004Inngår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 131, nr 4, 755-765 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protein phosphatase 2A (PP2A) can both positively and negatively influence the Ras/Raf/MEK/ERK signaling pathway, but its relevant substrates are largely unknown. In C. elegans, the PR55/B regulatory subunit of PP2A, which is encoded by sur-6, positively regulates Ras-mediated vulval induction and acts at a step between Ras and Raf. We show that the catalytic subunit (C) of PP2A, which is encoded by let-92, also positively regulates vulval induction. Therefore SUR-6/PR55 and LET-92/PP2A-C probably act together to dephosphorylate a Ras pathway substrate. PP2A has been proposed to activate the Raf kinase by removing inhibitory phosphates from Ser259 from Raf-1 or from equivalent Akt phosphorylation sites in other Raf family members. However, we find that mutant forms ofC. elegans LIN-45 RAF that lack these sites still require sur-6. Therefore, SUR-6 must influence Raf activity via a different mechanism. SUR-6 and KSR (kinase suppressor of Ras) function at a similar step in Raf activation but our genetic analysis suggests that KSR activity is intact in sur-6 mutants. We identify the kinase PAR-1 as a negative regulator of vulval induction and show that it acts in opposition to SUR-6 and KSR-1. In addition to their roles in Ras signaling, SUR-6/PR55 and LET-92/PP2A-C cooperate to control mitotic progression during early embryogenesis.

  • 39.
    Karlsson, Anders
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet).
    Olofsson, Anders
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Eneqvist, Therese
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet).
    Sauer-Eriksson, Elisabeth
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet).
    Cys114-linked dimers of transthyretin are compatible with amyloid formation.2005Inngår i: Biochemistry, ISSN 0006-2960, Vol. 44, nr 39, 13063-70 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Tyr114Cys substitution in the human plasma protein transthyretin leads to a particularly aggressive form of familial amyloidotic polyneuropathy. In a previous study we demonstrated that ATTR Tyr114Cys forms intermolecular disulfide bonds, which partly impair fibril formation and result in a more amorphous morphology. Apart from the introduced cysteinyl group in position 114, the native sequence contains one cysteine located at position 10. To deduce the role of intermolecular disulfide bridging in fibril formation we generated and characterized the TTR Cys10Ala/Tyr114Cys double mutant. Our results suggest that an intermolecular cysteine bridge at position 114 enhances the exposure of cysteine 10, thereby facilitating additional intermolecular cysteine assemblies. We also purified a disulfide-linked dimeric form of TTR Cys10Ala/Tyr114Cys, which was recognized by the anti-TTR amyloid-specific monoclonal antibody MAb (39-44). Moreover, this dimeric molecule can form protofibrils indistinguishable from the fibrils formed under reducing conditions, as judged by atomic force microscopy. Assuming that both molecules of the dimer are part of the core of the fibril, the assembly is incompatible with a preserved native or near-native dimeric interphase. Our findings raise the question of whether TTR-amyloid architecture is indeed the result of one highly stringent assembly of structures or if different fibrils may be built from different underlying structures.

  • 40.
    Keyser, Pia
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Borge Renberg, Karin
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    The Drosophila NFAT homolog is involved in salt stress tolerance.2007Inngår i: Insect Biochem Mol Biol, ISSN 0965-1748, Vol. 37, nr 4, 356-62 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The NFAT gene encodes the only homolog in Drosophila of the five human Nuclear Factors of Activated T-cells, NFAT1-5. Its rel homology domain is most similar to that of NFAT5, and like the latter it lacks conserved AP1 and calcineurin binding sites. Two promoters give rise to alternative transcripts that are ubiquitously expressed in several different tissues. We generated mutants for each transcript, as well as a mutant that lacks all functional NFAT expression. Only the null mutant generated a visible phenotype, indicating that the two transcripts are redundant. The mutants are sensitive to high salt diet and have enlarged anal pads in hypotonic solution, suggesting that NFAT, like mammalian NFAT5, is regulating the osmotic balance. A phylogenetic reconstruction puts the Drosophila gene near the root of the NFAT tree, indicating that regulation of tonicity may be an ancestral function of the NFAT family.

  • 41. Kleino, Anni
    et al.
    Myllymäki, Henna
    Kallio, Jenni
    Vanha-aho, Leena-Maija
    Oksanen, Kaisa
    Ulvila, Johanna
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Valanne, Susanna
    Rämet, Mika
    Pirk is a negative regulator of the Drosophila Imd pathway.2008Inngår i: J Immunol, ISSN 0022-1767, Vol. 180, nr 8, 5413-22 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    NF-kappaB transcription factors are involved in evolutionarily conserved signaling pathways controlling multiple cellular processes including apoptosis and immune and inflammatory responses. Immune response of the fruit fly Drosophila melanogaster to Gram-negative bacteria is primarily mediated via the Imd (immune deficiency) pathway, which closely resembles the mammalian TNFR signaling pathway. Instead of cytokines, the main outcome of Imd signaling is the production of antimicrobial peptides. The pathway activity is delicately regulated. Although many of the Imd pathway components are known, the mechanisms of negative regulation are more elusive. In this study we report that a previously uncharacterized gene, pirk, is highly induced upon Gram-negative bacterial infection in Drosophila in vitro and in vivo. pirk encodes a cytoplasmic protein that coimmunoprecipitates with Imd and the cytoplasmic tail of peptidoglycan recognition protein LC (PGRP-LC). RNA interference-mediated down-regulation of Pirk caused Imd pathway hyperactivation upon infection with Gram-negative bacteria, while overexpression of pirk reduced the Imd pathway response both in vitro and in vivo. Furthermore, pirk-overexpressing flies were more susceptible to Gram-negative bacterial infection than wild-type flies. We conclude that Pirk is a negative regulator of the Imd pathway.

  • 42. Kleino, Anni
    et al.
    Valanne, Susanna
    Ulvila, Johanna
    Kallio, Jenni
    Myllymäki, Henna
    Enwald, Heidi
    Stöven, Svenja
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten). Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi. Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Poidevin, Mickael
    Ueda, Ryu
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Lemaitre, Bruno
    Rämet, Mika
    Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Drosophila Imd pathway.2005Inngår i: EMBO J, ISSN 0261-4189, Vol. 24, nr 19, 3423-34 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Imd signaling cascade, similar to the mammalian TNF-receptor pathway, controls antimicrobial peptide expression in Drosophila. We performed a large-scale RNAi screen to identify novel components of the Imd pathway in Drosophila S2 cells. In all, 6713 dsRNAs from an S2 cell-derived cDNA library were analyzed for their effect on Attacin promoter activity in response to Escherichia coli. We identified seven gene products required for the Attacin response in vitro, including two novel Imd pathway components: inhibitor of apoptosis 2 (Iap2) and transforming growth factor-activated kinase 1 (TAK1)-binding protein (TAB). Iap2 is required for antimicrobial peptide response also by the fat body in vivo. Both these factors function downstream of Imd. Neither TAB nor Iap2 is required for Relish cleavage, but may be involved in Relish nuclear localization in vitro, suggesting a novel mode of regulation of the Imd pathway. Our results show that an RNAi-based approach is suitable to identify genes in conserved signaling cascades.

  • 43. Kläger, S L
    et al.
    Watson, A
    Achukwi, D
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hagen, H E
    Humoral immune response of Simulium damnosum s.l. following filarial and bacterial infections.2002Inngår i: Parasitology, ISSN 0031-1820, Vol. 125, nr Pt 4, 359-66 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The time-course of the humoral immune response of female blackflies after a challenge with bacteria, different Onchocerca microfilariae species, bacterial endotoxin and microfilarial extract was investigated. Strong bacteriolytic and growth inhibition activities against the Gram-positive bacterium Micrococcus luteus were induced by all agents. Specific differences were found in activity levels and time-course. Notably the endotoxin lipopolysaccharide (LPS) induced a very early, profound bacteriolytic and antibacterial response, which declined within a day after injection. In contrast, the bacteriolytic activities after Escherichia coli D31 and Onchocerca microfilariae infections were lower, but remained elevated over the observation period of 4 days. The bacteriolytic activity was correlated to a haemolymph protein with a molecular weight of around 14 kDa. Anti-Gram-positive activity in the E. coli infected group appeared within the first 6 h. However, it took 4 days in the microfilarial infected blackflies to reach significant levels. The active agent was identified to be a peptide with a molecular weight of around 4-4.5 kDa. Activity against the Gram-negative bacteria E. coli was detected in blackflies injected with E. coli D31, O. dukei microfilariae and microfilarial extract on days 1 and 4 after injection. The immune response in S. damnosum s.l. naturally infected via a bloodmeal on cattle supported the findings of the experimental infections. Similarities of the immune response kinetics between bacterial and filarial infections suggested that intracellular Wolbachia bacteria, released from microfilariae, could be responsible for the antibacterial response. This is supported by the observation that the induction of an immune response in the Drosophila melanogaster mbn-2 cell line by the filarial extract is blocked by polymyxin B, which forms inactive complexes with bacterial LPS.

  • 44. Kurucz, Eva
    et al.
    Márkus, Róbert
    Zsámboki, János
    Folkl-Medzihradszky, Katalin
    Darula, Zsuzsanna
    Vilmos, Péter
    Udvardy, Andor
    Krausz, Ildikó
    Lukacsovich, Tamás
    Gateff, Elisabeth
    Zettervall, Carl-Johan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Andó, István
    Nimrod, a putative phagocytosis receptor with EGF repeats in Drosophila plasmatocytes.2007Inngår i: Curr Biol, ISSN 0960-9822, Vol. 17, nr 7, 649-54 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The hemocytes, the blood cells of Drosophila, participate in the humoral and cellular immune defense reactions against microbes and parasites [1-8]. The plasmatocytes, one class of hemocytes, are phagocytically active and play an important role in immunity and development by removing microorganisms as well as apoptotic cells. On the surface of circulating and sessile plasmatocytes, we have now identified a protein, Nimrod C1 (NimC1), which is involved in the phagocytosis of bacteria. Suppression of NimC1 expression in plasmatocytes inhibited the phagocytosis of Staphylococcus aureus. Conversely, overexpression of NimC1 in S2 cells stimulated the phagocytosis of both S. aureus and Escherichia coli. NimC1 is a 90-100 kDa single-pass transmembrane protein with ten characteristic EGF-like repeats (NIM repeats). The nimC1 gene is part of a cluster of ten related nimrod genes at 34E on chromosome 2, and similar clusters of nimrod-like genes are conserved in other insects such as Anopheles and Apis. The Nimrod proteins are related to other putative phagocytosis receptors such as Eater and Draper from D. melanogaster and CED-1 from C. elegans. Together, they form a superfamily that also includes proteins that are encoded in the human genome.

  • 45. Kurucz, Eva
    et al.
    Váczi, B
    Márkus, R
    Laurinyecz, Barbara
    Vilmos, P
    Zsámboki, J
    Csorba, Kinga
    Gateff, Elisabeth
    Hultmark, D
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Andó, I
    Definition of Drosophila hemocyte subsets by cell-type specific antigens.2007Inngår i: Acta Biol Hung, ISSN 0236-5383, Vol. 58 Suppl, 95-111 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We analyzed the heterogeneity of Drosophila hemocytes on the basis of the expression of cell-type specific antigens. The antigens characterize distinct subsets which partially overlap with those defined by morphological criteria. On the basis of the expression or the lack of expression of blood cell antigens the following hemocyte populations have been defined: crystal cells, plasmatocytes, lamellocytes and precursor cells. The expression of the antigens and thus the different cell types are developmentally regulated. The hemocytes are arranged in four main compartments: the circulating blood cells, the sessile tissue, the lymph glands and the posterior hematopoietic tissue. Each hemocyte compartment has a specific and characteristic composition of the various cell types. The described markers represent the first successful attempt to define hemocyte lineages by immunological markers in Drosophila and help to define morphologically, functionally, spatially and developmentally distinct subsets of hemocytes.

  • 46.
    Kurucz, Eva
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Zettervall, Carl-Johan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Sinka, Rita
    Vilmos, Peter
    Pivarcsi, Andor
    Ekengren, Sophia
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hegedüs, Zoltán
    Ando, Istvan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hultmark, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hemese, a hemocyte-specific transmembrane protein, affects the cellular immune response in Drosophila.2003Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, nr 5, 2622-7 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have identified a previously undescribed transmembrane protein, Hemese, from Drosophila melanogaster blood cells (hemocytes), by using a monoclonal pan-hemocyte antibody. Heavy glycosylation is suggested by the heterogeneous size distribution, ranging between 37 and 70 kDa. Hemese expression is restricted to the cell surfaces of hemocytes of all classes, and to the hematopoietic organs. The sequence of the corresponding gene, Hemese (He), predicts a glycophorin-like protein of 15 kDa, excluding an N-terminal signal peptide, with a single hydrophobic transmembrane region. The extracellular region consists mainly of Ser/Thr-rich sequence of low complexity, with several potential O-glycosylation sites. Hemese contains phosphotyrosine and the cytoplasmic region has potential phosphorylation sites, suggesting an involvement in signal transduction. Depletion of Hemese by RNA interference has no obvious effect under normal conditions, but the cellular response to parasitic wasps is much enhanced. This finding indicates that Hemese plays a modulatory role in the activation or recruitment of the hemocytes.

  • 47. Lindmark, H
    et al.
    Johansson, K C
    Stöven, Svenja
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten). Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi. Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Engström, Ylva
    Söderhäll, Kenneth
    Enteric bacteria counteract lipopolysaccharide induction of antimicrobial peptide genes.2001Inngår i: J Immunol, ISSN 0022-1767, Vol. 167, nr 12, 6920-3 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The humoral immunity of Drosophila involves the production of antimicrobial peptides, which are induced by evolutionary conserved microbial molecules, like LPS. By using Drosophila mbn-2 cells, we found that live bacteria, including E. coli, Salmonella typhimurium, Erwinia carotovora, and Pseudomonas aeruginosa, prevented LPS from inducing antimicrobial peptide genes, while Micrococcus luteus and Streptococcus equi did not. The inhibitory effect was seen at bacterial levels from 20 per mbn-2 cell, while antimicrobial peptides were induced at lower bacterial concentrations (< or =2 bacteria per cell) also in the absence of added LPS. Gel shift experiment suggests that the inhibitory effect is upstream or at the level of the activation of the transcription factor Relish, a member of the NF-kappaB/Rel family. The bacteria have to be in physical contact with the cells, but not phagocytosed, to prevent LPS induction. Interestingly, the inhibiting mechanism is, at least for E. coli, independent of the type III secretion system, indicating that the inhibitory mechanism is unrelated to the one earlier described for YopJ from Yersinia.

  • 48. Little, Tom J
    et al.
    Hultmark, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Read, Andrew F
    Invertebrate immunity and the limits of mechanistic immunology.2005Inngår i: Nat Immunol, ISSN 1529-2908, Vol. 6, nr 7, 651-4 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rapid progress is being made in elucidating the molecular mechanisms involved in invertebrate immunity. This search for molecules runs the risk of missing important phenomena. In vertebrates, acquired protection and pathogen-specific responses were demonstrated experimentally long before the mechanisms responsible were elucidated. Without analogous experiments, mechanism-driven work may not demonstrate the full richness of invertebrate immunity.

  • 49.
    Lorén, Christina
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Umeå centrum för molekylär patogenes (UCMP).
    Scully, A
    Grabbe, C
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Edeen, PT
    Thomas, J
    McKeown, M
    Hunter, T
    Palmer, RH
    Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo.2001Inngår i: Genes to Cells, ISSN 1356-9597, Vol. 6, nr 6, 531-544 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 50. Lundström, Annika
    et al.
    Gallio, Marco
    Englund, Camilla
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Steneberg, Pär
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Hemphälä, Johanna
    Aspenström, Pontus
    Keleman, Krystyna
    Falileeva, Ludmilla
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten).
    Dickson, Barry J
    Samakovlis, Christos
    Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons2004Inngår i: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 18, nr 17, 2161-71 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Slit proteins steer the migration of many cell types through their binding to Robo receptors, but how Robo controls cell motility is not clear. We describe the functional analysis of vilse, a Drosophila gene required for Robo repulsion in epithelial cells and axons. Vilse defines a conserved family of RhoGAPs (Rho GTPase-activating proteins), with representatives in flies and vertebrates. The phenotypes of vilse mutants resemble the tracheal and axonal phenotypes of Slit and Robo mutants at the CNS midline. Dosage-sensitive genetic interactions between vilse, slit, and robo mutants suggest that vilse is a component of robo signaling. Moreover, overexpression of Vilse in the trachea of robo mutants ameliorates the phenotypes of robo, indicating that Vilse acts downstream of Robo to mediate midline repulsion. Vilse and its human homolog bind directly to the intracellular domains of the corresponding Robo receptors and promote the hydrolysis of RacGTP and, less efficiently, of Cdc42GTP. These results together with genetic interaction experiments with robo, vilse, and rac mutants suggest a mechanism whereby Robo repulsion is mediated by the localized inactivation of Rac through Vilse.

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