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  • 1
    Keywords: ACTIVATION ; ACTIN CYTOSKELETON ; ANTIGEN RECEPTOR ; ADAPTER PROTEIN ; CLASS-SWITCH RECOMBINATION ; SYNAPSE FORMATION ; PROTEIN-TYROSINE KINASE ; NON-ITAM TYROSINE ; IG-ALPHA ; LINKER PROTEIN
    Abstract: The adaptor Nck links receptor signaling to cytoskeleton regulation. Here we found that Nck also controlled the phosphatidylinositol-3-OH kinase (PI(3)K)-kinase Akt pathway by recruiting the adaptor BCAP after activation of B cells. Nck bound directly to the B cell antigen receptor (BCR) via the non-immunoreceptor tyrosine-based activation motif (ITAM) phosphorylated tyrosine residue at position 204 in the tail of the immunoglobulin-alpha component. Genetic ablation of Nck resulted in defective BCR signaling, which led to hampered survival and proliferation of B cells in vivo. Indeed, antibody responses in Nck-deficient mice were also considerably impaired. Thus, we demonstrate a previously unknown adaptor function for Nck in recruiting BCAP to sites of BCR signaling and thereby modulating the PI(3)K-Akt pathway in B cells.
    Type of Publication: Journal article published
    PubMed ID: 23913047
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  • 2
    Abstract: Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified approximately 16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeleton-related processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments.
    Type of Publication: Journal article published
    PubMed ID: 27155012
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  • 3
    Abstract: The MHC class I chain-related molecule A (MICA) is a highly polymorphic ligand for the activating natural killer (NK)-cell receptor NKG2D. A single nucleotide polymorphism causes a valine to methionine exchange at position 129. Presence of a MICA-129Met allele in patients (n = 452) undergoing hematopoietic stem cell transplantation (HSCT) increased the chance of overall survival (hazard ratio [HR] = 0.77, P = 0.0445) and reduced the risk to die due to acute graft-versus-host disease (aGVHD) (odds ratio [OR] = 0.57, P = 0.0400) although homozygous carriers had an increased risk to experience this complication (OR = 1.92, P = 0.0371). Overall survival of MICA-129Val/Val genotype carriers was improved when treated with anti-thymocyte globulin (HR = 0.54, P = 0.0166). Functionally, the MICA-129Met isoform was characterized by stronger NKG2D signaling, triggering more NK-cell cytotoxicity and interferon-gamma release, and faster co-stimulation of CD8(+) T cells. The MICA-129Met variant also induced a faster and stronger down-regulation of NKG2D on NK and CD8(+) T cells than the MICA-129Val isoform. The reduced cell surface expression of NKG2D in response to engagement by MICA-129Met variants appeared to reduce the severity of aGVHD.
    Type of Publication: Journal article published
    PubMed ID: 26483398
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  • 4
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; Germany ; human ; INHIBITION ; SYSTEM ; SITE ; PROTEIN ; PROTEINS ; INFECTION ; INDUCTION ; BINDING ; CYCLE ; SEQUENCE ; treatment ; SUSCEPTIBILITY ; ACIDS ; ENTRY ; virus ; ESCHERICHIA-COLI ; CELL-LINE ; LINE ; REGION ; MUTATIONS ; EXCHANGE ; PEPTIDES ; REPLICATION ; AMINO-ACIDS ; specificity ; POINT MUTATIONS ; BINDING-SITE ; MAP ; LOSSES ; LARGE ENVELOPE PROTEIN ; MYRISTYLATION ; PRE-S1 DOMAIN ; RECEPTOR-BINDING ; TUPAIA HEPATOCYTES ; VIRAL SURFACE PROTEIN
    Abstract: Insights into the early infection events of the human hepatitis B (HBV) and hepatitis delta virus (HDV) have been limited because of the lack of a cell culture system supporting the full replication cycle for these important pathogens. The human hepatoma cell line HepaRG allows the experimental induction of a differentiated state, thereby gaining susceptibility toward HBV and HDV infection. We recently identified HBV envelope protein-derived lipopeptides comprising amino acids 2 though 48 of the preS-domain of the L-surface protein, which block infection already at picomolar concentrations. To map the responsible sequence for the peptides' activity we describe an Escherichia coli expression system that permits myristoylation and investigated recombinant HBVpreS-GST fusion proteins with deletion- and point-mutations for their ability to prevent HBV and HDV infection. We found that (1) a myristoylated HBVpreS/2-48-GST fusion protein efficiently interferes with HBV infection of HepaRG cells; (2) deletions and point mutations in the highly conserved preS1 sequence between amino acids 11 through 21 result in the loss of infection inhibition activity, (3) hepatitis B viruses carrying single amino acid exchanges within this region lose infectivity; and (4) HDV infection of HepaRG cells can be inhibited by myristoylated HBVpreS peptides with the same specificity. In conclusion, HBV and HDV use at least one common step to enter hepatocytes and require a highly conserved preS1-sequence within the L-protein. This step is exceptionally sensitive toward inactivation by acylated HBVpreS1 peptides, which therefore represent a novel group of entry inhibitors that could be used for the treatment of hepatitis B and D
    Type of Publication: Journal article published
    PubMed ID: 16557545
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  • 5
    Keywords: LUNG-CANCER ; TRANSCRIPTION FACTORS ; ADAPTER PROTEINS ; CONSTITUTIVE ACTIVATION ; ACUTE MYELOGENOUS LEUKEMIA ; ANTIGEN RECEPTOR ; PHOSPHOINOSITIDE 3-KINASE ; ACUTE MYELOID-LEUKEMIA ; PROTEIN-TYROSINE KINASE ; PROTOONCOGENE PRODUCT
    Abstract: Spleen tyrosine kinase (Syk) induces cell survival and proliferation in a high proportion of acute myeloid leukemia (AML) blasts, but the underlying molecular events of Syk signaling have not been investigated. Proteomic techniques have allowed us to identify the multiprotein complex that is nucleated by constitutively active Syk in AML cells. This complex differs from the B-lymphoid Syk interactome with respect to several proteins, especially the integrin receptor Mac-1, the Fc-gamma receptor I (FcgammaRI), and the transcription factors STAT3 and STAT5. We show in several AML cell line models that tonic signals derived from the Fc-gamma chain lead to Syk-dependent activation of STAT3 and STAT5, which in turn induces cell survival and proliferation. Moreover, stimulation of Mac-1 or FcgammaRI intensifies the constitutive Syk-mediated STAT3/5 activation in AML cells, a scenario likely to take place in the bone marrow niche. In accordance with these findings, we observed that beta2 integrins, including Mac-1, trigger proliferation of AML cells in an AML cell/stroma coculture model. Taken together, we identified an oncogenic integrin/Syk/STAT3/5 signaling axis that might serve as a therapeutic target of AML in the future.
    Type of Publication: Journal article published
    PubMed ID: 23509157
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  • 6
    ISSN: 0300-9629
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1017
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The hallmarks of dry skin (xerosis) are scaliness and loss of elasticity. Decreased hydration and a disturbed lipid content of the stratum corneum are also well-known features. The frequency of dry skin increases with ageing. The aim of this study was to examine if these known features of dry skin are related to changes in epidermal proliferation and differentiation. In addition, age-related changes in normal and in dry skin were examined; 62 volunteers were divided by clinical grading and biophysical measurements into groups with young/normal, young/dry, aged/normal and aged/dry skin. Biopsy samples from the lower legs (most severe dryness) were examined by two-dimensional gel electrophoresis and by immunohistochemistry for epidermal proliferation, epidermal keratins and cornified envelope proteins. There was a slight increase in proliferation in both groups with dry skin compared with normal skin of the corresponding age. In aged/normal compared with young/normal skin there was a significant decrease in proliferation. However, epidermal proliferation was the same in aged/dry skin as in young/normal skin. For epidermal differentiation, an age-independent decrease of keratins K1 and K10 and an associated increase in the basal keratins K5 and K14 was detected in dry skin. There was also an age-independent premature expression of the cornified envelope protein involucrin. In contrast, loricrin expression was not influenced by dry skin conditions. In summary, epidermal proliferation was significantly decreased in aged/normal compared with young/normal skin. Dry skin showed significant changes in the epidermal expression of basal and differentiation-related keratins, and a premature expression of involucrin irrespective of age.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1424
    Keywords: Key words: Energy transfer — Intrinsic tryptophans — Pyrene excimer formation — Membrane fluidity — Gramicidin incorporated liposomes — Microsomal membranes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract. The presence of proteins in lipid bilayers always decreases the excimer formation rate of pyrene and pyrene lipid analogues in a way that is related to the protein-to-lipid ratio. Energy transfer measurements from intrinsic tryptophans to pyrene have shown (Engelke et al., 1994), that in microsomal membranes, the excimer formation rate of pyrene and pyrene fatty acids is heterogeneous within the membrane plane, because a lipid layer of reduced fluidity surrounds the microsomal proteins. This study investigates whether of not liposomes prepared from egg yolk phosphatidylcholine with incorporated gramicidin A give results comparable to those from microsomal membranes. The results indicate that the influence of proteins on the lipid bilayer cannot be described by one unique mechanism: Small proteins such as gramicidin A obviously reduce the excimer formation rate by occupying neighboring positions of the fluorescent probe and thus decrease the pyrene collision frequency homogeneously in the whole membrane plane, while larger proteins are surrounded by a lipid boundary layer of lower fluidity than the bulk lipid. The analysis of the time-resolved tryptophan fluorescence of gramicidin A incorporated liposomes reveals, that the tryptophan quenching by pyrene is stronger for tryptophans located closely below the phospholipid headgroup region because of the pyrene enrichment in this area of the lipid bilayer.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-4994
    Keywords: Pyrene excimer formation ; resonance energy transfer ; tryptophan ; fluidity ; liver microsomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Membrane fluidity measurements based on excimer formation of pyrene and pyrene derivatives as a measure of lateral diffusion yield a decreased fluidity in the presence of proteins [1,2]. It was the aim of our study to investigate whether the reduced excimer formation is due to a rigidifying effect of proteins on the whole membrane or if the fluorophore mobility is hindered mainly in the immediate protein environment. Resonance energy transfer in microsomal membranes between intrinsic tryptophan residues and pyrene was used to study the excimer formation rate in the vicinity of proteins. The excimer-to-monomer fluorescence ratio after excitation via resonance energy transfer decreased compared to that observed for the direct excitation. The results suggest that, because of the reduced fluidity in the neighborhood of proteins, pyrene and pyrenedodecanoic acid do not diffuse homogeneously in the membrane plane.
    Type of Medium: Electronic Resource
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