title: Radil controls neutrophil adhesion and motility through β2-integrin activation.
abstract: Integrin activation is required to facilitate multiple adhesion-dependent functions of neutrophils, such as chemotaxis, which is critical for inflammatory responses to injury and pathogens. However, little is known about the mechanisms that mediate integrin activation in neutrophils. We show that Radil, a novel Rap1 effector, regulates β1- and β2-integrin activation and controls neutrophil chemotaxis. On activation and chemotactic migration of neutrophils, Radil quickly translocates from the cytoplasm to the plasma membrane in a Rap1a-GTP-dependent manner. Cells overexpressing Radil show a substantial increase in cell adhesion, as well as in integrin/focal adhesion kinase (FAK) activation, and exhibit an elongated morphology, with severe tail retraction defects. This phenotype is effectively rescued by treatment with either β2-integrin inhibitory antibodies or FAK inhibitors. Conversely, knockdown of Radil causes severe inhibition of cell adhesion, β2-integrin activation, and chemotaxis. Furthermore, we found that inhibition of Rap activity by RapGAP coexpression inhibits Radil-mediated integrin and FAK activation, decreases cell adhesion, and abrogates the long-tail phenotype of Radil cells. Overall, these studies establish that Radil regulates neutrophil adhesion and motility by linking Rap1 to β2-integrin activation.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Lunhua
authors.initials: L
authors.lastname: Liu
authors.forename: Wulin
authors.initials: W
authors.lastname: Aerbajinai
authors.forename: Syed M
authors.initials: SM
authors.lastname: Ahmed
authors.forename: Griffin P
authors.initials: GP
authors.lastname: Rodgers
authors.forename: Stephane
authors.initials: S
authors.lastname: Angers
authors.forename: Carole A
authors.initials: CA
authors.lastname: Parent
mesh_terms: D015153:Blotting, Western; D018821:CD18 Antigens / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D009154:Mutation; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D002352:Carrier Proteins; D008164:Luminescent Proteins; C548041:RADIL protein, human; D009240:N-Formylmethionine Leucyl-Phenylalanine; D020827:rap1 GTP-Binding Proteins