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AG Borggrefe

Über uns

AG


Transcriptional Regulation of Blood Cell Development

 

Unraveling the Molecular Mechanism of the Notch Signal Transduction Pathway

Notch signaling is an evolutionary conserved signal transduction pathway that plays pivotal roles in numerous aspects of cell differentiation, tissue homeostasis and tumorigenesis. In normal hematopoiesis Notch1 is essential for T-cell development and has been implicated in the maintenance of hematopoietic stem cells. At the molecular level, ligand binding induces the processing of the Notch transmembrane receptor resulting in the release of the intracellular domain of Notch (NICD), see also Figure 1. Subsequently, the NICD translocates to the nucleus, binds the transcription factor RBP-J and activates transcription of target genes. In the absence of the NICD, RBP-J actively represses Notch target genes through recruitment of corepressor complexes. My laboratory has extensively characterized this molecular switch (corepressor to coactivator) and characterized several Notch-cofactors (Oswald et al., 2005, Salat et al. 2008, Liefke et al. 2010, Wacker et al., 2010 and Jung et al., 2013).

 

Chromatin players in the Notch response:

Over the last few years we and other investigators have postulated that chromatin-based mechanisms play a key role in the control of Notch target gene expression (Borggrefe and Liefke, 2012). Some of the key questions are how histone methyltransferases and demethylases dynamically regulate histone methylation at specific target genes, how gene responsiveness is set up by activating and repressing methylation marks and how these enzymes work in concert with histone acetyltransferases (HATs), deacetylases (HDACs), kinases and phosphatases. We have for example demonstrated that Notch signaling dynamically regulates H3K4 methylation and showed that the H3K4 histone demethylase KDM5A plays a crucial role in this process (Liefke et al., 2010).

notch

 

Characterization of the RBP-J repressor complex in leukemogenesis

Notch signaling have been implicated in the development of several forms of leukemia. We could identify ETO as part of the RBP-J corepressor complex. A chromosomal fusion protein AML1/ETO can disrupt the corepressor complex leading to a derepression of Notch target genes. We want to further characterize the underlying molecular mechanism that leads to leukemogenesis.

 

Characterization of the Notch-coactivator complex

Taking a biotinylation-tagging approach, we have isolated the RBP-J/Notch coactivator complex and characterized several of its components. For example, we have described the non-coding RNA Steroid-Responsive Activator (SRA) as part of the RBP/Notch coactivator complex. This complex is key in recruiting the acetyltransferase p300 that places the activating acetyl-marks on histones (Jung et al., 2013).

Posttranslational modifications (ubiquitinylation, phosphorylation, hydroxylation and acetylation) play a major role in the Notch response and tightly control the Notch coactivator turnover. Mutations in the C-terminal PEST-domain, that stabilize the Notch protein, have been detected in human T-ALL patients. In future, we will focus on the role of Notch modifying enzymes, which posttranslationally modify Notch itself, thereby controlling amplitude and duration of the Notch response.

 

buch

AG Preissner

Über uns

AG Preissner 2018

Our main areas of research: 


Cellular and molecular communications in the vascular system in relation to inflammation

  • The role of matrix proteins, adhesion receptors and protease systems in mechanisms of angiogenesis, atherogenesis and vascular remodeling
  • New adhesion receptors for recruitment and transmigration/invasion of leukocytes in inflammation
  • Mechanism of tumor-necrosis-factor shedding
  • Pathological mechanisms of late complications of diabetes, role of advanced glycation endproducts

 

Mechanisms in innate immunity and body defense with particular emphasis on haemostasis and blood coagulation

  • New intravascular and extravascular initiation mechanisms of blood coagulation
  • Extracellular RNA and NET between defense and disease: contribution in thrombosis, edema, angiogenesis, arteriogenesis and atherosclerosis
  • New intervention strategies in vascular diseases using RNase and DNase
  • Cellular haemostasis and protease receptor-mediated reactions


 

Bacterial invasion and anti-adhesive strategies for anti-microbial therapies

  • Wound healing mechanisms and bacterial infection in vertebrates and insects
  • Bacterial adhesion, invasion and evasion strategies with emphasis on Eap

 

Research Areas of the Preissner Group:

 

The scientific interests and active research of the group are concerned with the contribution of innate immunity processes in host-pathogen interactions, inflammation, wound healing and thrombosis, particularly dedicated to cardiovascular and pulmonary diseases. In this context, the as yet unrecognized role of self-extracellular nucleic acids as alarm signals in disease is a major part of our work, documented by many recent publications, particularly achieved by multiple collaborations with different laboratories worldwide.

 

A major part of our current work concentrates on the role of “danger-associated molecular patterns” (DAMPs) such as endogenous extracellular nucleic acids as alarm signals in situations of microbe-host interactions or in diseases of the vascular and cardiopulmonary system. To this end, our group has made seminal discoveries to show that self-extracellular RNA serves as a potent cofactor in thrombosis, tissue edema, cardiac ischemia-reperfusion injury or tumor progression and that RNase1 administration is successful as novel therapeutic intervention in such pathological situations. Likewise, together with cooperation partners in Munich (Steffen Massberg and Bernd Engelmann), extracellular DNA/histone complexes (released from neutrophils as bacteria-killing “neutrophil extracellular traps”, NETs) have been shown to be principal intravascular initiators of arterial as well as venous thrombosis. Together, these novel concepst have had a major impact on our mechanistic understanding of cardiovascular and inflammatory diseases as well as for the use of potentially novel drugs such as RNase1 or DNase.

 

Previously, our work was concerned with new regulatory mechanisms of blood coagulation and thrombosis at the vessel wall and particularly with the diverse properties of vitronectin, a multifunctional adhesive as regulatory factor in vascular biology. Here, several discoveries, concerned with the scaffolding functions of vitronectin as matricellular protein and its receptors (integrins and non-integrins such as the urokinase receptor), were made, particularly related to inflammation, angiogenesis, and the regulation of other vascular processes.

 

We further described new adhesion receptors (such as JAM-3 or RAGE) in the context of cell-to-cell communication in inflammatory reactions as being responsible for seminal reactions of the leukocyte recruitment process in innate immunity. Our research on a specific adherence protein of Staphylococcus aureus, designated “Extracellular adherence protein” (Eap), which presents strong anti-inflammatory and anti-angiogenic functions, has gained insights into bacteria-protective/evasion properties of this factor. Moreover, Eap has successfully been used as a novel anti-inflammatory approach in diverse animal models for therapeutic intervention in wound healing, multiple sclerosis, psoriasis or tumor metastasis. 

  

Previous and Current Research Activities of the Preissner Group:

 

1983-1988

Regulation of thrombin function at the vascular endothelium, influence of thrombomodulin, serpins and proteoglycans

1985-1999

Structure-function relationships of vitronectin and its receptors, humoral and cellular activities of the matricellular protein

since 1997

Bacteria-host interactions, bacterial adhesion and evasion strategies in infection

1988-1998

Plasminogen activator inhibitor-1 (PAI-1) and its interactions with cells and proteins, role of PAI-1 in cell motility and cell functions

1996-2006

Functions of urokinase receptor as coordinator of cell adhesion and pericellular proteolysis, regulation of ß2-integrin-dependent leukocyte functions

1996-2004

Mechanisms of pathological angiogenesis, diabetic retinopathy (coop Diabetology)

1998-2004

Mechanisms of high-molecular-weight-kininogen as anti-adhesive and anti-inflammatory protein

2001-2011

Structure and function of Factor VII-activating protease (FSAP)

since 2002

Anti-inflammatory and anti-angiogenic mechanisms of “Extracellular adherence protein” (Eap) from Staphylococcus aureus (coop Medical Microbiology)

2002-2006

Discovery and functions of new cell adhesion receptors (JAM-3, RAGE), role in inflammation and thrombosis (coop Transfusion Medicine)

2003-2010

New RNA-binding autoantigens in neurological disorders (coop Neurology)

2004-2010

Vascular stem cells and mechanisms of placenta formation (coop Gynecology)

since 2002

New induction processes in haemostasis and blood coagulation, mechanisms of "Intra-vascular Tissue Factor Pathway"

since 2002

Extracellular RNA as endogenous alarm signal in body defense and cardio-vascular diseases

since 2005

Inflammatory and degenerative mechanisms in lung diseases, cellular activities of intrinsic coagulation in lung fibrosis (coop Pulmonology)

since 2006

“Neutrophil extracellular traps” (NET) in arterial and venous thrombosis and vascular diseases; cytotoxicity of histones

 

AG Schmitz

Über uns

Introduction

Our group investigates the molecular mechanisms allowing the transmission of upstream signals to changes in gene expression and chromatin organisation. We study these processes using the NF-κB transcription factor system and the family of stress-regulated homeodomain-interacting protein kinases (HIPKs) as model systems. We investigate how external signals lead to the activation of protein kinases, which then transmit their signals into the nucleus where they regulate transcription factors and epigenetic events. These studies employ a large array of biochemical and cell biological in vitro and cell culture experiments, but also use clinical samples and model organisms for the validation of our findings. The NF-κB and HIPK signal transmission systems are important regulators of the stress response and cell proliferation and are thus found to be dysregulated in a variety of proliferative diseases such as cancer or fibrosis. We are always interested in applications of prospective PhD students or postdocs who are willing to join a hard-working and competitive team with a friendly atmosphere.

 

Research

1) The first focus of our research is centered on NF-κB. This transcription factor contributes to the mounting of an effective immune response, but is also involved in the regulation of cell migration, proliferation and apoptosis. The implication of NF-κB in central biological processes and its extraordinary connectivity to other signaling pathways raise a need for highly controlled regulation of NF-κB activity at several levels. The so-called noncanonical IKK kinases IKKε and TBK1 function to trigger the activity of various proinflammatory transcription factors including the NF-κB subunit p65 and IRFs. The analysis of the noncanonical IKKs and their adaptor proteins is of special relevance for the lab, as their overexpression in pathophysiological conditions triggers oncogenic transformation of breast cancer cells and mediates chemoresistance of non-small cell lung cancer and HER2+ breast cancer cells. Mechanistically, overexpression of noncanonical IKKs triggers the expression of anti-apoptotic signaling, stimulates cell proliferation and also allows PI3K-independent direct phosphorylation of the pro-survival kinase AKT. In addition, the constitutive activity of noncanonical IKKs allows for autocrine cytokine circuits that fuel tumor cell growth and cell migration.

NF-κB activity is also regulated within the nucleus. In a collaboration with the group of Michael Kracht (Giessen) we use genome-wide analyses to clarify the contribution of cofactors and upstream kinases for the chromatin recruitment of NF-κB p65 and chromatin modification. We also investigate the genome-wide recruitment of posttranslationally modified NF-κB p65 and a DNA-binding mutant to reveal their physiological function for transcriptional activation and chromatin association. We test the functional consequences of a stimulus-induced conformational switch of NF-κB p65 using a recently identified conformation-specific antibody. These experiments will allow conclusions on the significance of posttranslational modifications, context-specific conformation and DNA-binding for p65 functions, allowing an improved understanding of the molecular mechanisms underlying the plasticity of NF-κB-dependent gene regulation in healthy and diseased cells.

 

Schema

 

2) The second focus is on the HIPK family of serine/threonine kinases. They function as integrators of a wide variety of stress signals. A number of conditions representing precarious situations such as DNA damage, hypoxia, reactive oxygen intermediates and metabolic stress affect the function of HIPKs. The kinases function as integrators for these stress signals and feed them into many different downstream effector pathways that serve to cope with these precarious situations. Their central role as signaling hubs with the ability to shape many downstream effector pathways frequently implies them in proliferative diseases such as cancer or fibrosis. Using genome-wide assays we study how HIPKs are anchored at specific sites on the genome and how they reprogram gene expression. We have identified chromatin binding sites for a member of the HIPK family using ChIP-Seq and found that the majority of the binding motifs overlaps with a sequence recognized by a ubiquitously expressed transcription factor. The relative contribution of this transcription factor for chromatin attachment of the kinase and the functional relevance for HIPK-regulated gene expression and modification of neighbouring chromatin regions are under investigation. We also study the contribution of these kinases for the coupling of transcription initiation, elongation and the further processing/degradation of the resulting transcripts. This will be of special relevance in certain brain tumors which are addicted to the constitutive activity of HIPKs. As kinases can be targeted by small molecule inhibitors, the development of specific and reversible HIPK inhibitors is a further goal of the lab.

Words

AG Tikkanen

Über uns

AG Tikkanen

Rare Diseases Research Group

The main research interest of our group are the molecular mechanisms of rare diseases and development of personalized therapies for such diseases. The spectrum of diseases in our research focus include lysosomal storage disorders (aspartylglucosaminuria, neuronal ceroid lipofuscinoses), disorders of neurotransmitter metabolism (SSADH deficiency), and autoimmune diseases (Pemphigus). In addition, the molecular mechanisms of cancers, especially those dependent on MAP kinase signaling, are addressed in our group. 

 

Aspartylglucosaminuria (R. Tikkanen and A. Banning)

Aspartylglucosaminuria (AGU) is a rare genetic disorder caused by mutations in the gene encoding for the lysosomal enzyme aspartylglucosaminidase (AGA). AGU patients are born seemingly normal, but within the first years of life, they start lagging behind in their development and become increasingly handicapped and intellectually disabled by early adulthood. Currently, no approved therapies are available for AGU.  

Our group focuses on characterization of the molecular consequences of the AGU mutations, with the aim of developing individual therapies for AGU. Our approaches include pharmacological chaperones (PC) and nonsense read-through drugs, and we are also involved in developing gene therapy for AGU. So far, we have developed two PC therapies that are currently tested in patients (Banning et al. 2016). An investigator-initiated clinical trial with one of these substances is currently undergoing in Finland, together with Dr. Minna Laine, a child neurologist at Helsinki University Hospital (see: https://pediatricresearchcenter.helsinki.fi/137-a-novel-therapy-trial-for-agu-disease-at-huch.html). For patients exhibiting nonsense mutations combined with certain missense mutations, we have shown that substances that inhibit the nonsense-mediated decay of mRNA and induce a translational read-through of the nonsense codon are beneficial in AGU and result in increased enzyme activity in patient cells (Banning et al. 2018). One of these substances is also currently tested in an individual clinical trial.

Gene therapy approach for AGU is currently being developed in collaboration with UTSW researchers, especially Dr. Steven Gray (see: https://www.med.unc.edu/genetherapy/research-laboratories/gray-lab/) .

 

Neuronal Ceroid Lipofuscinoses (R. Tikkanen and A. Zakrzewicz)

Neuronal ceroid lipofuscinoses (NCL) are a group of lysosomal storage disorders that result in a severe developmental delay associated with vision loss and epileptic seizures that are difficult to control. Depending on the respective gene defect, these diseases show a different age of onset and disease progression and are classified into various forms (CLN1 - CLN14). Our group is interested in the classic late infantile (cLINCL, CLN2) and juvenile (JNCL, CLN3) forms. Therapies are available for only very few NCL forms.

We have previously shown that specific membrane lipids termed gangliosides exhibit altered amounts in JNCL (Somogyi et al. 2018). Especially the ganglioside GM3 accumulates in high amounts, whereas other gangliosides such as GM1 are reduced. Since balanced amounts of various gangliosides are vital for normal brain development, we are currently testing if modulation of ganglioside amounts in NCLs might have a therapeutic effect.

Also in NCL diseases, we are interested in developing therapies that are based on similar strategies as described above for AGU, namely read-through therapies and pharmacological chaperones. Since certain nonsense mutations are very common especially in cLINCL patients, the read-through approach may provide a means to treat a large number of patients with the same drug. 

 

SSADH Deficiency (R. Tikkanen)

Succinyl semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter GABA. SSADH deficiency (SSADH-D) is a genetic disorder caused by mutations in the gene encoding the SSADH enzyme. In the absence of SSADH activity, GABA and its metabolite GHB accumulate in the tissues and cause mainly neuronal and muscular deficits. Our current research interests are the characterization of the molecular consequences of SSADH mutations and testing of various therapy options in cell culture models. As with AGU and NCLs, we are interested in identifying PC substances that would restore the missing SSADH activity, and probing for the read-through therapies. In addition, we are developing strategies suitable for enzyme replacement and gene therapy for SSADH-D.             

 

Function of Flotillin Proteins in Cell Adhesion: Molecular Mechanisms of Pemphigus Vulgaris (R. Tikkanen and A. Banning)

Our current work includes the characterization of the molecular function of the flotillin family of proteins. Flotillins were originally described as neuronal regeneration proteins that are upregulated in the regenerating axons of gold fish retinal ganglion cells after a lesion of the optic nerve and thus named “reggies” for regeneration. Later studies have shown that flotillins are ubiquitously expressed, highly conserved and associated with membrane rafts. Our previous work has focused on characterization of flotillin function in signal transduction and cell adhesion. We have shown that flotillins are involved in both cell-matrix and cell-cell adhesion (Banning et al. 2018, Völlner et al. 2016). We could show that flotillins are involved in the regulation of desmosomal adhesion in the epidermis, and they interact with the desmosomal cadherin proteins and plakoglobin (Völlner et al. 2016).

Our current research focuses on elucidating the molecular mechanism of how desmosomal adhesion is regulated by flotillins, and how flotillins modulate the desmosomal adhesion in the severe autoimmune skin disease Pemphigus Vulgaris (PV). In PV, autoantibodies against desmosomal adhesion proteins, mainly desmoglein-3, cause severe blistering of the epidermis and mucosa due to loss of desmosomal adhesion in epidermal keratinocytes. The mechanisms of adhesion loss are as yet not completely characterized, but signaling and vesicle trafficking are likely to play a role. Flotillins are known to be involved in both signaling and membrane trafficking, and we are currently studying how flotillins modulate these processes in the context of Pemphigus. We are members in the DFG-funded Research Focus FOR 2497 “Pemphigus - from Pathogenesis to Therapy (Pegasus)”. (www.pegasus-dfg.de). In addition to their role in the regulation of desmosomes in the epidermis, we are also interested in how flotillins affect desmosomal adhesion in the cardiac tissue (Kessler et al. 2018).      

Flotillins in Cancer and as Regulators of MAP Kinase Signaling

Our recent findings show that depletion of flotillin-1 results in a severe impairment of EGF receptor signaling. Not only the activation of the EGF receptor is inhibited, but also the downstream signaling towards the MAP kinase cascade (Amaddii et al. 2012). We could show that flotillin-1 directly interacts with several proteins of the MAP kinase pathway, including CRAF, MEK1 and ERK2 and thus most likely functions in regulating the signaling at the level of MAPK signalosomes. Flotillins are frequently overexpressed in various types of cancers, and our research aims at characterizing the link between flotillin function and cancer/metastasis formation.


Recent Publications (selection)

  1. Somogyi A, Petcherski A, Beckert B, Huebecker M, Priestman DA, Banning A, Cotman SL, Platt FM, Ruonala MO, Tikkanen R. (2018) Altered expression of ganglioside metabolizing enzymes results in GM3 ganglioside accumulation in cerebellar cells of a mouse model of juvenile neuronal ceroid lipofuscinosis. Int J Mol Sci, 19, 625; doi:10.3390/ijms19020625
  2. Banning A, Schiff M, Tikkanen R. (2018) Amlexanox Provides a Potential Therapy for Nonsense Mutations in the Lysosomal Storage Disorder Aspartylglucosaminuria. BBA - Molecular Basis of Disease, pii: S0925-4439(17)30463-5. doi: 10.1016/j.bbadis.2017.12.014
  3. Banning A, Babuke T, Kurrle N, Meister M, Ruonala MO, Tikkanen R. (2018) Flotillins regulate focal adhesions by interacting with α-actinin and by influencing the activation of Focal Adhesion Kinase. Cells, 7, 28; doi:10.3390/cells7040028
  4. Kessler EA, van Stuijvenberg L, van Bavel JJA, van Bennekom J, Zwartsen A, Rivaud MA, Vink A, Efimov IA, van Tintelen JP, Remme CA, Marc A. Vos MA, Banning A, de Boer TP, Tikkanen R, van Veen TAB. (2018) Flotillins in the intercalated disc are potential modulators of cardiac excitability. In press, J Mol Cell Cardiol 2018 Nov 16. pii: S0022-2828(18)30540-6. doi: 10.1016/j.yjmcc.2018.11.007.
  5. Meister M, Baenfer S, Gärtner U, Koskimies J, Amaddii M, Jacob R, Tikkanen R. (2017) Regulation of cargo transfer between ESCRT-0 and ESCRT-I complexes by flotillin-1 during endosomal sorting of ubiquitinated cargo. Oncogenesis 6, e344; doi:10.1038/oncsis.2017.47
  6. Banning A, König JF, Gray SJ, Tikkanen R. (2017) Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production . Int J Mol Sci, 18, 706; doi:10.3390/ijms18040706
  7. Banning A, Gülec C, Rouvinen J, Gray SJ, Tikkanen R. (2016) Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria. Sci. Rep. 6, 37583; doi: 10.1038/srep37583
  8. Völlner F, Ali J, Kurrle N, Exner Y, Eming R, Hertl M, Banning A, Tikkanen R. (2016) Loss of flotillin expression results in weakened desmosomal adhesion and Pemphigus vulgaris-like localisation of desmoglein-3 in human keratinocytes. Sci Rep, 6, 28820; DOI:10.1038/srep28820
  9. Kapahnke M, Banning A, Tikkanen R. (2016) Random splicing of several exons caused by a single base change in the target exon of CRISPR/Cas9 mediated gene knockout. Cells 5, 45; doi:10.3390/cells5040045
  10. Banning A, Regenbrecht CRA, Tikkanen R. (2014) Increased activity of mitogen activated protein kinase pathway in flotillin-2 knockout mouse. Cell Signal, 26(2), 198-207. doi: 10.1016/j.cellsig.2013.11.001
  11. Meister M, Zuk A, Tikkanen R. (2014) Role of dynamin and clathrin in cellular trafficking of flotillins. FEBS J, 281, 2956–2976. doi: 10.1111/febs.12834
  12. John BA, Meister M, Banning A, Tikkanen R. (2014) Flotillins bind to the Dileucine Sorting Motif of BACE1 and influence its endosomal Sorting. FEBS J, 281, 2074–2087. doi: 10.1111/febs.12763.
  13. 13.   Mooz J, Oberoi-Khanuja TK, Harms GS, Wang W, Tikkanen R, Jaiswal BS, Seshagiri S, Rajalingam K. (2014) Dimerization of ARAF promotes MAPK activation and cell migration. Science Signaling, 7(337):ra73. doi: 10.1126/scisignal.2005484
  14. Fork C, Hitzel J, Nichols BJ, Tikkanen R, Brandes RP. (2014) Flotillin-1 facilitates Toll-like receptor 3 signaling in human endothelial cells. Basic Res Cardiol, 109:439. doi: 10.1007/s00395-014-0439-4
  15. Kurrle N, Völlner F, Eming R, Hertl M, Banning A, Tikkanen R. (2013) Flotillins directly interact with γ-catenin and regulate cell-cell adhesion. PLoS ONE, 8(12):e84393 doi: 10.1371/journal.pone.0084393
  16. Amaddii M*, Meister M*, Banning A, Tomasovic A, Mooz J, Rajalingam K, Tikkanen R. (2012) Flotillin-1/reggie-2 plays a dual role in the activation of receptor tyrosine kinase/MAP kinase signaling. J Biol Chem, 287(10):7265-78
  17. Chapuy B, Tikkanen R, Mühlhausen C, Wenzel D, von Figura K, Höning S. (2008) The AP-1 and AP-3 adaptor complexes mediate sorting of melanosomal and lysosomal membrane proteins into distinct post-Golgi trafficking pathways. Traffic, 9: 1157-1172
  18. Icking A, Amaddii M, Ruonala M, Höning S, Tikkanen R. (2007) Polarized transport of Alzheimer Amyloid Precursor Protein is mediated by adaptor complex AP-1B. Traffic, 8: 285-296
  19. Neumann-Giesen C, Fernow I, Amaddii M, Tikkanen R. (2007) Role of EGF-induced Tyrosine Phosphorylation of Reggie-1/Flotillin-2 in Cell Spreading and Signaling to Actin Cytoskeleton. J Cell Sci, 120: 395-406
  20. Babuke T, Tikkanen R. (2007) Dissecting the molecular function of reggie/flotillin proteins. Eur J Cell Biol, 86: 525–532 (review)
  21. Schilling K, Opitz N, Wiesenthal A, Oess S, Tikkanen R, Müller-Esterl W, Icking A. (2006) Translocation of endothelial NO synthase involves a ternary complex with caveolin-1 and NOSTRIN. Mol Biol Cell, 17: 3870-80
  22. Jakob V, Schreiner A, Tikkanen R, Starzinski-Powitz A. (2006) Targeting of transmembrane protein shrew-1 to adherens junctions is controlled by cytoplasmic sorting motifs. Mol Biol Cell, 17: 3397-3408
  23. Hoeller D, Crosetto N, Blagoev B, Raiborg C, Tikkanen R, Wagner S, Kowanetz K, Breitling R, Mann M, Stenmark H, Dikic I. (2006) Regulation of ubiquitin-binding proteins by monoubiquitination. Nature Cell Biol, 8: 163-169
 

 

For a complete list of publications of Ritva Tikkanen, see Pubmed

 

AG Wygrecka

Über uns

Forschungsschwerpunkte

 

Our research focuses on the pathomechanisms of pulmonary fibrosis and acute inflammatory lung diseases, in particular, on the role proteases and their receptors in the aforementioned pathological conditions. The overall goal of our translationally oriented research activities is: i) to elucidate the importance of hemostatic proteases and their receptors in epithelial cell-fibroblast and macrophage-fibroblast communication during pathological lung tissue remodeling and ii) to reveal the molecular basis of the crosstalk between protease receptors and other signaling pathways known to play a pivotal role in lung inflammation and fibrosis. The ultimate aim of our activities is to develop new therapeutic concepts based on these investigations. 

     WygreckaLunge

     

    Proteinanalytik AG Lochnit

    Über uns

    Die Arbeitsgruppe Protein Analytik verfügt über langjährige Erfahrung gel-gestützter Protein-Analytik. Das methodische Repertoir umfaßt 2D-Gelelektrophorese, densitometrische Analyse von Proteomen sowie die automatisierte Proteinidentifizierung mittels MALDI-TOF Massenspektrometrie. Daneben verfügt die Arbeitsgruppe über zahlreiche weitere proteinanalytische Methodiken wie z.B. die N-terminale Edman-Sequenzierung.

    Die Methoden stehen interessierten wissenschaftlichen Arbeitsgruppen in der Regel im Rahmen von Kooperationen zur Verfügung. Als Service Einrichtung existieren zahlreiche Kooperationen mit Arbeitsgruppen aus den Klinischen Forschergruppen, den Sonderforschungsbereichen und dem Exzellenzcluster des Fachbereichs Medizin der JLU Giessen sowie internationalen Graduiertenkollegs. Darüber hinaus bestehen zahlreiche Kooperationen mit Arbeitsgruppen anderen Fachbereichen sowie Universitäten auf nationaler und internationaler Ebene.

    Daneben bietet die Protein Analytik regelmäßig Workshops zu Methoden der Proteinanalytik für die Nachwuchsausbildung an.

    Prof. Dr. Günter Lochnit ist Mitglied der "International Giessen Graduate School for the Life Sciences (GGL)" sowie der HUPO-Initiative iMOP.

    Forschungsschwerpunkt der Arbeitsgruppe Protein Analytik ist die Methodenentwicklung in der Proteinanalytik mit dem Schwerpunkt der Automatisierung und Analyse von posttranslationalen Modifkationen. Ein Fokus liegt in der Analyse von posttranslationalen Modifikationen von Krankheitserregern, welches das Überleben des Pathoges im Wirt ermöglichen. Modellsystem ist hierbei der freilebende Bodennematode Caenorhabditis elegans. Zu dessen Untersuchung ist der Protein Analytik ein C. elegans Lab angeschlossen.