title: Changes in membrane sphingolipid composition modulate dynamics and adhesion of integrin nanoclusters.
abstract: Sphingolipids are essential constituents of the plasma membrane (PM) and play an important role in signal transduction by modulating clustering and dynamics of membrane receptors. Changes in lipid composition are therefore likely to influence receptor organisation and function, but how this precisely occurs is difficult to address given the intricacy of the PM lipid-network. Here, we combined biochemical assays and single molecule dynamic approaches to demonstrate that the local lipid environment regulates adhesion of integrin receptors by impacting on their lateral mobility. Induction of sphingomyelinase (SMase) activity reduced sphingomyelin (SM) levels by conversion to ceramide (Cer), resulting in impaired integrin adhesion and reduced integrin mobility. Dual-colour imaging of cortical actin in combination with single molecule tracking of integrins showed that this reduced mobility results from increased coupling to the actin cytoskeleton brought about by Cer formation. As such, our data emphasizes a critical role for the PM local lipid composition in regulating the lateral mobility of integrins and their ability to dynamically increase receptor density for efficient ligand binding in the process of cell adhesion.
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Postbox 9101, 6500 HB Nijmegen, The Netherlands.
authors: Christina
authors: C
authors: Eich
authors: ICFO-Institut de Ciencies Fotoniques, Mediterranean Technology Park, 08860 Castelldefels (Barcelona), Spain.
authors: Carlo
authors: C
authors: Manzo
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Postbox 9101, 6500 HB Nijmegen, The Netherlands.
authors: Sandra
authors: S
authors: de Keijzer
authors: Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Postbox 9101, 6500 HB Nijmegen, The Netherlands.
authors: Gert-Jan
authors: GJ
authors: Bakker
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Postbox 9101, 6500 HB Nijmegen, The Netherlands.
authors: Inge
authors: I
authors: Reinieren-Beeren
authors: ICFO-Institut de Ciencies Fotoniques, Mediterranean Technology Park, 08860 Castelldefels (Barcelona), Spain.|ICREA-Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.
authors: Maria F
authors: MF
authors: García-Parajo
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Postbox 9101, 6500 HB Nijmegen, The Netherlands.
authors: Alessandra
authors: A
authors: Cambi
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism; D004058:Diffusion; D005677:G(M1) Ganglioside / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D000199:Actins; D002518:Ceramides; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D013107:Sphingolipids; D013109:Sphingomyelins; D005677:G(M1) Ganglioside; D013108:Sphingomyelin Phosphodiesterase