title: The scaffold protein Cybr is required for cytokine-modulated trafficking of leukocytes in vivo.
abstract: Trafficking and cell adhesion are key properties of cells of the immune system. However, the molecular pathways that control these cellular behaviors are still poorly understood. Cybr is a scaffold protein highly expressed in the hematopoietic/immune system whose physiological role is still unknown. In vitro studies have shown it regulates LFA-1, a crucial molecule in lymphocyte attachment and migration. Cybr also binds cytohesin-1, a guanine nucleotide exchange factor for the ARF GTPases, which affects actin cytoskeleton remodeling during cell migration. Here we show that expression of Cybr in vivo is differentially modulated by type 1 cytokines during lymphocyte maturation. In mice, Cybr deficiency negatively affects leukocytes circulating in blood and lymphocytes present in the lymph nodes. Moreover, in a Th1-polarized mouse model, lymphocyte trafficking is impaired by loss of Cybr, and Cybr-deficient mice with aseptic peritonitis have fewer cells than controls present in the peritoneal cavity, as well as fewer leukocytes leaving the bloodstream. Mutant mice injected with Moloney murine sarcoma/leukemia virus develop significantly larger tumors than wild-type mice and have reduced lymph node enlargement, suggesting reduced cytotoxic T-lymphocyte migration. Taken together, these data support a role for Cybr in leukocyte trafficking, especially in response to proinflammatory cytokines in stress conditions.
authors.affiliation: Neural Development Group, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA. coppolav@ncifcrf.gov
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Barrick
authors.forename: Sara
authors.initials: S
authors.lastname: Bobisse
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Rodriguez-Galan
authors.forename: Michela
authors.initials: M
authors.lastname: Pivetta
authors.forename: Della
authors.initials: D
authors.lastname: Reynolds
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Palko
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Esteban
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D016207:Cytokines / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008980:Moloney murine sarcoma virus; D010538:Peritonitis / Q000276:immunology / Q000473:pathology; D012192:Retroviridae Infections / Q000276:immunology / Q000473:pathology; D012513:Sarcoma, Experimental / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology; D014412:Tumor Virus Infections / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D003598:Cytoskeletal Proteins