title: Regulation of conformer-specific activation of the integrin LFA-1 by a chemokine-triggered Rho signaling module.
abstract: Regulation of the affinity of the beta(2) integrin LFA-1 by chemokines is critical to lymphocyte trafficking, but the signaling mechanisms that control this process are not well understood. Here we investigated the signaling events controlling LFA-1 affinity triggering by chemokines in human primary T lymphocytes. We found that the small GTPase Rac1 mediated chemokine-induced LFA-1 affinity triggering and lymphocyte arrest in high endothelial venules. Unexpectedly, another Rho family member, Cdc42, negatively regulated LFA-1 activation. The Rho effectors PLD1 and PIP5KC were also critical to LFA-1 affinity modulation. Notably, PIP5KC was found to specifically control the transition of LFA-1 from an extended low-intermediate state to a high-affinity state, which correlated with lymphocyte arrest. Thus, chemokines control lymphocyte trafficking by triggering a Rho-dependent signaling cascade leading to conformer-specific modulation of LFA-1 affinity.
authors.affiliation: University of Verona, School of Medicine, Department of Pathology, Division of General Pathology, Verona 37134, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bolomini-Vittori
authors.forename: Alessio
authors.initials: A
authors.lastname: Montresor
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giagulli
authors.forename: Donald
authors.initials: D
authors.lastname: Staunton
authors.forename: Barbara
authors.initials: B
authors.lastname: Rossi
authors.forename: Marianna
authors.initials: M
authors.lastname: Martinello
authors.forename: Gabriela
authors.initials: G
authors.lastname: Constantin
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016169:Lymphocyte Function-Associated Antigen-1; D034741:RNA, Small Interfering; D054460:rho-Associated Kinases