title: Evidence of zeta protein kinase C involvement in polymorphonuclear neutrophil integrin-dependent adhesion and chemotaxis.
abstract: Classical chemoattractants and chemokines trigger integrin-dependent adhesion of blood leukocytes to vascular endothelium and also direct subsequent extravasation and migration into tissues. In studies of human polymorphonuclear neutrophil responses to formyl peptides and to interleukin 8, we show evidence of involvement of the atypical zeta protein kinase C in the signaling pathway leading to chemoattractant-triggered actin assembly, integrin-dependent adhesion, and chemotaxis. Selective inhibitors of classical and novel protein kinase C isozymes do not prevent chemoattractant-induced neutrophil adhesion and chemotaxis. In contrast, chelerythrine chloride and synthetic myristoylated peptides with sequences based on the endogenous zeta protein kinase C pseudosubstrate region block agonist-induced adhesion to fibrinogen, chemotaxis and F-actin accumulation. Biochemical analysis shows that chemoattractants trigger rapid translocation of zeta protein kinase C to the plasma membrane accompanied by rapid but transient increase of the kinase activity. Moreover, pretreatment with C3 transferase, a specific inhibitor of Rho small GTPases, blocks zeta but not alpha protein kinase C plasma membrane translocation. Synthetic peptides from zeta protein kinase C also inhibit phorbol ester-induced integrin-dependent adhesion but not NADPH-oxidase activation, and C3 transferase pretreatment blocks phorbol ester-triggered translocation of zeta but not alpha protein kinase C. These data suggest the involvement of zeta protein kinase C in chemoattractant-induced leukocyte integrin-dependent adhesion and chemotaxis. Moreover, they highlight a potential link between atypical protein kinase C isozymes and Rho signaling pathways leading to integrin-activation.
authors.affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, and the Digestive Disease Center, Department of Medicine, Stanford University, Stanford, California 94305, USA. clauda@borgoroma.univr.it
authors.forename: C
authors.initials: C
authors.lastname: Laudanna
authors.forename: D
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: T
authors.initials: T
authors.lastname: Liron
authors.forename: G
authors.initials: G
authors.lastname: Constantin
authors.forename: E C
authors.initials: EC
authors.lastname: Butcher
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001905:Botulinum Toxins; D002448:Cell Adhesion; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000502:physiology*; D009504:Neutrophils / Q000201:enzymology* / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000099221:Protein Kinase C zeta
chemical_list: D036002:ADP Ribose Transferases; D000199:Actins; D001905:Botulinum Toxins; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D016023:Integrins; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D000099221:Protein Kinase C zeta; C085379:rho GTPase-activating protein; C063007:exoenzyme C3, Clostridium botulinum