title: Src-dependent Syk activation controls CD69-mediated signaling and function on human NK cells.
abstract: CD69 C-type lectin receptor represents a functional triggering molecule on activated NK cells, capable of directing their natural killing function. The receptor-proximal signaling pathways activated by CD69 cross-linking and involved in CD69-mediated cytotoxic activity are still poorly understood. Here we show that CD69 engagement leads to the rapid and selective activation of the tyrosine kinase Syk, but not of the closely related member of the same family, ZAP70, in IL-2-activated human NK cells. Our results indicate the requirement for Src family kinases in the CD69-triggered activation of Syk and suggest a role for Lck in this event. We also demonstrate that Syk and Src family tyrosine kinases control the CD69-triggered tyrosine phosphorylation and activation of phospholipase Cgamma2 and the Rho family-specific exchange factor Vav1 and are responsible for CD69-triggered cytotoxicity of activated NK cells. The same CD69-activated signaling pathways are also observed in an RBL transfectant clone, constitutively expressing the receptor. These data demonstrate for the first time that the CD69 receptor functionally couples to the activation of Src family tyrosine kinases, which, by inducing Syk activation, initiate downstream signaling pathways and regulate CD69-triggered functions on human NK cells.
authors.affiliation: Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pisegna
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Pirozzi
authors.forename: Benedetta
authors.initials: B
authors.lastname: Cinque
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cifone
authors.forename: Stefania
authors.initials: S
authors.lastname: Morrone
authors.forename: Mario
authors.initials: M
authors.lastname: Piccoli
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Gabriella
authors.initials: G
authors.lastname: Palmieri
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation / Q000276:immunology; D004792:Enzyme Precursors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology*; D037181:Lectins, C-Type; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D051379:Mice; D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases / Q000502:physiology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018797:Cell Cycle Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D037181:Lectins, C-Type; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D000072377:Syk Kinase; D010738:Type C Phospholipases; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases; D000099192:CD69 Antigens; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; C000606896:SYK protein, human; C000606897:Syk protein, mouse; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse