title: Integrins Influence the Size and Dynamics of Signaling Microclusters in a Pyk2-dependent Manner.
abstract: Integrin engagement on lymphocytes initiates "outside-in" signaling that is required for cytoskeleton remodeling and the formation of the synaptic interface. However, the mechanism by which the "outside-in" signal contributes to receptor-mediated intracellular signaling that regulates the kinetics of granule delivery and efficiency of cytolytic activity is not well understood. We have found that variations in ICAM-1 expression on tumor cells influence killing kinetics of these cells by CD16.NK-92 cytolytic effectors suggesting that changes in integrin ligation on the effector cells regulate the kinetics of cytolytic activity by the effector cells. To understand how variations of the integrin receptor ligation may alter cytolytic activity of CD16.NK-92 cells, we analyzed molecular events at the contact area of these cells exposed to planar lipid bilayers that display integrin ligands at different densities and activating CD16-specific antibodies. Changes in the extent of integrin ligation on CD16.NK-92 cells at the cell/bilayer interface revealed that the integrin signal influences the size and the dynamics of activating receptor microclusters in a Pyk2-dependent manner. Integrin-mediated changes of the intracellular signaling significantly affected the kinetics of degranulation of CD16.NK-92 cells providing evidence that integrins regulate the rate of target cell destruction in antibody-dependent cell cytotoxicity (ADCC).
authors.affiliation: From the Departments of Microbiology and Immunology and.
authors.forename: Maria
authors.initials: M
authors.lastname: Steblyanko
authors.affiliation: From the Departments of Microbiology and Immunology and.
authors.forename: Nadia
authors.initials: N
authors.lastname: Anikeeva
authors.affiliation: the Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.affiliation: Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and.
authors.forename: James H
authors.initials: JH
authors.lastname: Keen
authors.affiliation: From the Departments of Microbiology and Immunology and Yuri.Sykulev@Jefferson.edu.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sykulev
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity; D018821:CD18 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology; D008024:Ligands; D008051:Lipid Bilayers / Q000737:chemistry; D008214:Lymphocytes / Q000166:cytology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; C573420:ICAM1 protein, human; D016023:Integrins; D008024:Ligands; D008051:Lipid Bilayers; D017452:Receptors, IgG; D018799:Intercellular Adhesion Molecule-1; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases
keywords: ADCC; Cytotoxic lymphocytes; Integrin receptors; cellular immune response; immunology; killing kinetics; lymphocyte; natural killer cells (NK cells); signaling; signaling microclusters