title: Proline-rich tyrosine kinase 2 and Rac activation by chemokine and integrin receptors controls NK cell transendothelial migration.
abstract: Protein tyrosine kinase activation is an important requisite for leukocyte migration. Herein we demonstrate that NK cell binding to endothelium activates proline-rich tyrosine kinase 2 (Pyk-2) and the small GTP binding protein Rac that are coupled to integrin and chemokine receptors. Chemokine-mediated, but not integrin-mediated, Pyk-2 and Rac activation was sensitive to pretreatment of NK cells with pertussis toxin, a pharmacological inhibitor of G(i) protein-coupled receptors. Both Pyk-2 and Rac are functionally involved in chemokine-induced NK cell migration through endothelium or ICAM-1 or VCAM-1 adhesive proteins, as shown by the use of recombinant vaccinia viruses encoding dominant negative mutants of Pyk-2 and Rac. Moreover, we found that Pyk-2 is associated with the Rac guanine nucleotide exchange factor Vav, which undergoes tyrosine phosphorylation upon integrin triggering. Finally, we provide direct evidence for the involvement of Pyk-2 in the control of both chemokine- and integrin-mediated Rac activation. Collectively, our results indicate that Pyk-2 acts as a receptor-proximal link between integrin and chemokine receptor signaling, and the Pyk-2/Rac pathway plays a pivotal role in the control of NK cell transendothelial migration.
authors.affiliation: Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, Rome, Italy. angela.gismondi@uniroma1.it
authors.forename: Angela
authors.initials: A
authors.lastname: Gismondi
authors.forename: Jordan
authors.initials: J
authors.lastname: Jacobelli
authors.forename: Raffaele
authors.initials: R
authors.lastname: Strippoli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mainiero
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.forename: Loredana
authors.initials: L
authors.lastname: Cifaldi
authors.forename: Mario
authors.initials: M
authors.lastname: Piccoli
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
mesh_terms: D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051418:Focal Adhesion Kinase 2; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D010766:Phosphorylation; D011392:Proline / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology
chemical_list: D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D014443:Tyrosine; D011392:Proline; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; D020744:rac GTP-Binding Proteins