TY  - JOUR
A1  - Butt, Elke
A1  - Stempfle, Katrin
A1  - Lister, Lorenz
A1  - Wolf, Felix
A1  - Kraft, Marcella
A1  - Herrmann, Andreas B.
A1  - Viciano, Cristina Perpina
A1  - Weber, Christian
A1  - Hochhaus, Andreas
A1  - Ernst, Thomas
A1  - Hoffmann, Carsten
A1  - Zernecke, Alma
A1  - Frietsch, Jochen J.
T1  - Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia
JF  - Cells
N2  - The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.
KW  - LASP1
KW  - CXCR4
KW  - AKT1
KW  - CML
KW  - breast cancer
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200638
SN  - 2073-4409
VL  - 9
IS  - 2
ER  - 
TY  - JOUR
A1  - Chubanov, Vladimir
A1  - Ferioli, Silvia
A1  - Wisnowsky, Annika
A1  - Simmons, David G.
A1  - Leitzinger, Christin
A1  - Einer, Claudia
A1  - Jonas, Wenke
A1  - Shymkiv, Yuriy
A1  - Gudermann, Thomas
A1  - Bartsch, Harald
A1  - Braun, Attila
A1  - Akdogan, Banu
A1  - Mittermeier, Lorenz
A1  - Sytik, Ludmila
A1  - Torben, Friedrich
A1  - Jurinovic, Vindi
A1  - van der Vorst, Emiel P. C.
A1  - Weber, Christian
A1  - Yildirim, Önder A.
A1  - Sotlar, Karl
A1  - Schürmann, Annette
A1  - Zierler, Susanna
A1  - Zischka, Hans
A1  - Ryazanov, Alexey G.
T1  - Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival
JF  - eLife
N2  - Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.
KW  - signalling pathways
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164987
VL  - 5
ER  - 
TY  - JOUR
A1  - Soehnlein, Oliver
A1  - Drechsler, Maik
A1  - Döring, Yvonne
A1  - Lievens, Dirk
A1  - Hartwig, Helene
A1  - Kemmerich, Klaus
A1  - Ortega-Gómez, Almudena
A1  - Mandl, Manuela
A1  - Vijayan, Santosh
A1  - Projahn, Delia
A1  - Garlichs, Christoph D.
A1  - Koenen, Rory R.
A1  - Hristov, Mihail
A1  - Lutgens, Esther
A1  - Zernecke, Alma
A1  - Weber, Christian
T1  - Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes
JF  - EMBO Molecular Medicine
N2  - We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical \((inflammatory/Gr1^{hi})\) or non-classical \((resident/Gr1^{lo})\) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient \((Apoe^{-/-})\) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient \(Apoe^{-/-}\) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or \(CX_3CR1\) in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.
KW  - hypercholeterolemia
KW  - CCR2
KW  - atherosclerosis
KW  - chemokine
KW  - accumulation
KW  - subsets
KW  - inflammatory sites
KW  - fractalkine
KW  - marcophages
KW  - mobilization
KW  - monocyte
KW  - recruitment
KW  - bone-marrow
KW  - atheriosclerotic lesions
KW  - hyperlipedemic mice
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122204
SN  - 1757-4676
VL  - 5
ER  - 
TY  - JOUR
A1  - Tilstam, Pathricia V.
A1  - Gijbels, Marion J.
A1  - Habbeddine, Mohamed
A1  - Cudejko, Celine
A1  - Asare, Yaw
A1  - Theelen, Wendy
A1  - Zhou, Baixue
A1  - Döring, Yvonne
A1  - Drechsler, Maik
A1  - Pawig, Lukas
A1  - Simsekyilmaz, Sakine
A1  - Koenen, Rory R.
A1  - de Winther, Menno P. J.
A1  - Lawrence, Toby
A1  - Bernhagen, Jürgen
A1  - Zernecke, Alma
A1  - Weber, Christian
A1  - Noels, Heidi
T1  - Bone Marrow-Specific Knock-In of a Non-Activatable Ikkα Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice
JF  - PLOS ONE
N2  - Background: The Ikkα kinase, a subunit of the NF-kappa B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk alpha mutant knock-in on haematopoiesis and atherosclerosis in mice. 
Methods and Results: Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant Ikkα gene (Ikkα(AA/AA) Apoe(-/-)) or with Ikkα(+/+) Apoe(-/-) BM as control and were fed a high-cholesterol diet for 8 or 13 weeks. Interestingly, haematopoietic profiling by flow cytometry revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in Ikkα(AA/AA) Apoe(-/-) BM-chimeras, whereas the naive T-cell population was increased. Surprisingly, no differences were observed in the size, stage or cellular composition of atherosclerotic lesions in the aorta and aortic root of Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) BM-transplanted mice, as shown by histological and immunofluorescent stainings. Necrotic core sizes, apoptosis, and intracellular lipid deposits in aortic root lesions were unaltered. In vitro, BM-derived macrophages from Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) mice did not show significant differences in the uptake of oxidized low-density lipoproteins (oxLDL), and, with the exception of Il-12, the secretion of inflammatory proteins in conditions of Tnf-α or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable. 
Conclusion: Our data reveal an important and previously unrecognized role of haematopoietic Ikkα kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikkα AA mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikkα kinase activity alone does not represent a therapeutic approach.
KW  - NF-KAPPA-B
KW  - regulatory T cells
KW  - indoleamine 2,3-dioxygenase
KW  - dendritic cells
KW  - gene expression
KW  - increases atherosclersosis
KW  - receptor
KW  - inhibition
KW  - pathway
KW  - beta
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117450
VL  - 9
IS  - 2
ER  -