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Your search keyword '"Fässler, Reinhard"' showing total 1,159 results
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1,159 results on '"Fässler, Reinhard"'

13. Caskin2 is a novel talin- and Abi1-binding protein that promotes cell motility.

Author

Wei Wang, Atherton, Paul, Kreft, Maaike, te Molder, Lisa, van der Poel, Sabine, Hoekman, Liesbeth, Celie, Patrick, Joosten, Robbie P., Fässler, Reinhard, Perrakis, Anastassis, and Sonnenberg, Arnoud

Subjects
CELL motility, SCAFFOLD proteins, CELL migration, EXTRACELLULAR matrix, PROTEINS, FOCAL adhesions
Abstract

Talin (herein referring collectively to talin 1 and 2) couples the actomyosin cytoskeleton to integrins and transmits tension to the extracellular matrix. Talin also interacts with numerous additional proteins capable of modulating the actin-integrin linkage and thus downstream mechanosignaling cascades. Here, we demonstrate that the scaffold protein Caskin2 interacts directly with the R8 domain of talin through its C-terminal LD motif. Caskin2 also associates with the WAVE regulatory complex to promote cell migration in an Abi1-dependent manner. Furthermore, we demonstrate that the Caskin2-Abi1 interaction is regulated by growth factor-induced phosphorylation of Caskin2 on serine 878. In MCF7 and UACC893 cells, which contain an amplification of CASKIN2, Caskin2 localizes in plasma membrane-associated plaques and around focal adhesions in cortical microtubule stabilization complexes. Taken together, our results identify Caskin2 as a novel talin-binding protein that might not only connect integrin-mediated adhesion to actin polymerization but could also play a role in crosstalk between integrins and microtubules. [ABSTRACT FROM AUTHOR]

Published
2024
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18. The Mechanism of Kindlin-Mediated Activation of Integrin αIIbβ3

Author

Ye, Feng, Petrich, Brian G, Anekal, Praju, Lefort, Craig T, Kasirer-Friede, Ana, Shattil, Sanford J, Ruppert, Raphael, Moser, Markus, Fässler, Reinhard, and Ginsberg, Mark H

Subjects
Biochemistry and Cell Biology, Biological Sciences, Hematology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Blood Platelets, Cytoskeletal Proteins, HEK293 Cells, Humans, Ligands, Membrane Proteins, Mice, Neoplasm Proteins, Platelet Glycoprotein GPIIb-IIIa Complex, Protein Structure, Tertiary, Recombinant Proteins, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

Increased ligand binding to cellular integrins ("activation") plays important roles in processes such as development, cell migration, extracellular matrix assembly, tumor metastasis, hemostasis, and thrombosis. Integrin activation encompasses both increased integrin monomer affinity and increased receptor clustering and depends on integrin-talin interactions. Loss of kindlins results in reduced activation of integrins. Kindlins might promote talin binding to integrins through a cooperative mechanism; however, kindlins do not increase talin association with integrins. Here, we report that, unlike talin head domain (THD), kindlin-3 has little effect on the affinity of purified monomeric αIIbβ3, and it does not enhance activation by THD. Furthermore, studies with ligands of varying valency show that kindlins primarily increase cellular αIIbβ3 avidity rather than monomer affinity. In platelets or nucleated cells, loss of kindlins markedly reduces αIIbβ3 binding to multivalent but not monovalent ligands. Finally, silencing of kindlins reduces the clustering of ligand-occupied αIIbβ3 as revealed by total internal reflection fluorescence and electron microscopy. Thus, in contrast to talins, kindlins have little primary effect on integrin αIIbβ3 affinity for monovalent ligands and increase multivalent ligand binding by promoting the clustering of talin-activated integrins.

Published
2013

24. CD98hc facilitates B cell proliferation and adaptive humoral immunity.

Author

Cantor, Joseph, Browne, Cecille D, Ruppert, Raphael, Féral, Chloé C, Fässler, Reinhard, Rickert, Robert C, and Ginsberg, Mark H

Subjects
B-Lymphocytes, Plasma Cells, Cells, Cultured, Animals, Mice, Transgenic, Mice, Mitogen-Activated Protein Kinase 3, Integrins, Lymphocyte Activation, Cell Differentiation, Cell Proliferation, Antibody Formation, Protein Binding, Biological Transport, Active, Cyclin-Dependent Kinase Inhibitor p27, Fusion Regulatory Protein 1, Heavy Chain, 1.1 Normal biological development and functioning, Immunology
Abstract

The proliferation of antigen-specific lymphocytes and resulting clonal expansion are essential for adaptive immunity. We report here that B cell-specific deletion of the heavy chain of CD98 (CD98hc) resulted in lower antibody responses due to total suppression of B cell proliferation and subsequent plasma cell formation. Deletion of CD98hc did not impair early B cell activation but did inhibit later activation of the mitogen-activated protein kinase Erk1/2 and downregulation of the cell cycle inhibitor p27. Reconstitution of CD98hc-deficient B cells with CD98hc mutants showed that the integrin-binding domain of CD98hc was required for B cell proliferation but that the amino acid-transport function of CD98hc was dispensable for this. Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored the appearance of CD98hc in vertebrates.

Published
2009

44. Surface-induced phase separation of reconstituted nascent integrin clusters on lipid membranes.

Author

Chiao-Peng Hsu, Aretz, Jonas, Hordeichyk, Arsenii, Fässler, Reinhard, and Bausch, Andreas R.

Subjects
PHASE separation, MEMBRANE lipids, INTEGRINS, CELL membranes, FOCAL adhesions
Abstract

Integrin adhesion complexes are essential membrane-associated cellular compartments for metazoan life. The formation of initial integrin adhesion complexes is a dynamic process involving focal adhesion proteins assembled at the integrin cytoplasmic tails and the inner leaflet of the plasma membrane. The weak multivalent protein interactions within the complex and with the plasma membrane suggest that liquid-liquid phase separation could play a role in the nascent adhesion assembly. Here, we report that solid-supported lipid membranes supplemented with phosphoinositides induce the phase separation of minimal integrin adhesion condensates composed of integrin β1 tails, kindlin, talin, paxillin, and FAK at physiological ionic strengths and protein concentrations. We show that the presence of phosphoinositides is key to enriching kindlin and talin on the lipid membrane, which is necessary to further induce the phase separation of paxillin and FAK at the membrane. Our data demonstrate that lipid membrane surfaces set the local solvent conditions for steering the membranelocalized phase separation even in a regime where no condensate formation of proteins occurs in bulk solution. [ABSTRACT FROM AUTHOR]

Published
2023
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