title: JAK tyrosine kinases promote hierarchical activation of Rho and Rap modules of integrin activation.
abstract: Lymphocyte recruitment is regulated by signaling modules based on the activity of Rho and Rap small guanosine triphosphatases that control integrin activation by chemokines. We show that Janus kinase (JAK) protein tyrosine kinases control chemokine-induced LFA-1- and VLA-4-mediated adhesion as well as human T lymphocyte homing to secondary lymphoid organs. JAK2 and JAK3 isoforms, but not JAK1, mediate CXCL12-induced LFA-1 triggering to a high affinity state. Signal transduction analysis showed that chemokine-induced activation of the Rho module of LFA-1 affinity triggering is dependent on JAK activity, with VAV1 mediating Rho activation by JAKs in a Gαi-independent manner. Furthermore, activation of Rap1A by chemokines is also dependent on JAK2 and JAK3 activity. Importantly, activation of Rap1A by JAKs is mediated by RhoA and PLD1, thus establishing Rap1A as a downstream effector of the Rho module. Thus, JAK tyrosine kinases control integrin activation and dependent lymphocyte trafficking by bridging chemokine receptors to the concurrent and hierarchical activation of the Rho and Rap modules of integrin activation.
authors.affiliation: Department of Pathology and Diagnostics, Division of General Pathology, School of Medicine, and 2 The Center for Biomedical Computing, University of Verona, Verona 37134, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Montresor
authors.forename: Matteo
authors.initials: M
authors.lastname: Bolomini-Vittori
authors.forename: Lara
authors.initials: L
authors.lastname: Toffali
authors.forename: Barbara
authors.initials: B
authors.lastname: Rossi
authors.forename: Gabriela
authors.initials: G
authors.lastname: Constantin
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
mesh_terms: D002448:Cell Adhesion; D054377:Chemokine CXCL12 / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism / Q000502:physiology; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D053612:Janus Kinases / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology; D010739:Phospholipase D / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D020668:rap GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D053612:Janus Kinases; D010739:Phospholipase D; C106801:phospholipase D1; D020668:rap GTP-Binding Proteins; D020741:rho GTP-Binding Proteins