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.
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.
Giagulli
Cinzia
C
Department of Pathology, Faculty of Medicine, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy.
Scarpini
Elio
E
Ottoboni
Linda
L
Narumiya
Shuh
S
Butcher
Eugene C
EC
Constantin
Gabriela
G
Laudanna
Carlo
C
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
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