title: RhoA and zeta PKC control distinct modalities of LFA-1 activation by chemokines: critical role of LFA-1 affinity triggering in lymphocyte in vivo homing.
abstract: Chemokines regulate rapid leukocyte adhesion by triggering a complex modality of integrin activation. We show that the small GTPase RhoA and the atypical zeta PKC differently control lymphocyte LFA-1 high-affinity state and rapid lateral mobility induced by chemokines. Activation of LFA-1 high-affinity state and lateral mobility is controlled by RhoA through the activity of distinct effector regions, demonstrating that RhoA is a central point of diversification of signaling pathways leading to both modalities of LFA-1 triggering. In contrast, zeta PKC controls LFA-1 lateral mobility but not affinity triggering. Blockade of the 23-40 RhoA effector region prevents induction of LFA-1 high-affinity state as well as lymphocyte arrest in Peyer's patch high endothelial venules. Thus, RhoA controls the induction of LFA-1 high-affinity state by chemokines independently of zeta PKC, and this is critical to support chemokine-regulated homing of circulating lymphocytes.
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giagulli
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Linda
authors.initials: L
authors.lastname: Ottoboni
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Butcher
authors.forename: Gabriela
authors.initials: G
authors.lastname: Constantin
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D018925:Chemokines / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D013997:Time Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D018925:Chemokines; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020742:rhoA GTP-Binding Protein; D000099221:Protein Kinase C zeta