title: Agonist leukadherin-1 increases CD11b/CD18-dependent adhesion via membrane tethers.
abstract: Integrin CD11b/CD18 is a key adhesion receptor that mediates leukocyte migration and immune functions. Leukadherin-1 (LA1) is a small molecule agonist that enhances CD11b/CD18-dependent cell adhesion to its ligand ICAM-1. Here, we used single-molecule force spectroscopy to investigate the biophysical mechanism by which LA1-activated CD11b/CD18 mediates leukocyte adhesion. Between the two distinct populations of CD11b/CD18:ICAM-1 complex that participate in cell adhesion, the cytoskeleton(CSK)-anchored elastic elements and the membrane tethers, we found that LA1 enhanced binding of CD11b/CD18 on K562 cells to ICAM-1 via the formation of long membrane tethers, whereas Mn(2+) additionally increased ICAM-1 binding via CSK-anchored bonds. LA1 activated wild-type and LFA1(-/-) neutrophils also showed longer detachment distances and time from ICAM-1-coated atomic force microscopy tips, but significantly lower detachment force, as compared to the Mn(2+)-activated cells, confirming that LA1 primarily increased membrane-tether bonds to enhance CD11b/CD18:ICAM-1 binding, whereas Mn(2+) induced additional CSK-anchored bond formation. The results suggest that the two types of agonists differentially activate integrins and couple them to the cellular machinery, providing what we feel are new insights into signal mechanotransduction by such agents.
authors: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida.
authors: Emrah
authors: E
authors: Celik
authors: Mohd Hafeez
authors: MH
authors: Faridi
authors: Vinay
authors: V
authors: Kumar
authors: Shashank
authors: S
authors: Deep
authors: Vincent T
authors: VT
authors: Moy
authors: Vineet
authors: V
authors: Gupta
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000737:chemistry / Q000378:metabolism*; D008345:Manganese / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000378:metabolism; D011485:Protein Binding; D013867:Thiohydantoins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001565:Benzoates; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D013867:Thiohydantoins; C000589733:leukadherin-1; D018799:Intercellular Adhesion Molecule-1; D008345:Manganese