title: SOS1, ARHGEF1, and DOCK2 rho-GEFs Mediate JAK-Dependent LFA-1 Activation by Chemokines.
abstract: JAK-dependent activation of the rho module of integrin affinity triggering mediates chemokine-induced leukocyte adhesion. However, the signaling events linking JAKs to rho small GTPase activation by chemokines is still incompletely described. In this study, we show that son of sevenless 1 (SOS1), rho guanine nucleotide exchange factor (GEF)1 (ARHGEF1), and dedicator of cytokinesis (DOCK)2 GEFs mediate CXCL12-induced LFA-1 activation in human primary T lymphocytes. Downregulated expression of SOS1, ARHGEF1, and DOCK2 impairs LFA-1-mediated rapid T lymphocyte adhesion as well as underflow arrest on ICAM-1 induced by CXCL12. Moreover, LFA-1 affinity triggering by CXCL12 is impaired by SOS1, ARHGEF1, and DOCK2 downregulation. Notably, the three GEFs are all critically involved in chemokine-induced RhoA and Rac1 activation, thus suggesting the occurrence of a SOS1 specificity shift in the context of chemokine signaling. Accordingly, SOS1, ARHGEF1, and DOCK2 are tyrosine phosphorylated upon chemokine signaling with timing coherent with rapid LFA-1 affinity activation. Importantly, chemokine-induced tyrosine phosphorylation of these GEFs is fully mediated by JAK protein tyrosine kinases. Unexpectedly, and differently from VAV1, tyrosine phosphorylation of SOS1, ARHGEF1, and DOCK2 is completely inhibited by pertussis toxin pretreatment, thus suggesting different routes of rho-GEF triggering upon CXCR4 engagement. Taken together, these findings reveal a deeper level of complexity in the rho-signaling module, with at least four different rho-GEFs cooperating in the regulation of chemokine-induced integrin activation, possibly suggesting the emergence of stochastic concurrency in signaling mechanisms controlling leukocyte trafficking.
authors.affiliation: Department of Medicine, University of Verona, Verona 37134, Italy.|Center for Biomedical Computing, University of Verona, Verona 37134, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Toffali
authors.affiliation: Department of Medicine, University of Verona, Verona 37134, Italy.|Center for Biomedical Computing, University of Verona, Verona 37134, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Montresor
authors.affiliation: Department of Medicine, University of Verona, Verona 37134, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Mirenda
authors.affiliation: Italian Foundation for Cancer Research Institute for Molecular Oncology, Milan 20139, Italy; and.|Department of Oncology and Hemato-Oncology, Italian Database of Operational Losses, University of Milan, Milan 20142, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scita
authors.affiliation: Department of Medicine, University of Verona, Verona 37134, Italy; carlo.laudanna@univr.it.|Center for Biomedical Computing, University of Verona, Verona 37134, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
mesh_terms: D015153:Blotting, Western; D018925:Chemokines / Q000276:immunology; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000276:immunology; D006801:Humans; D047468:Immunoprecipitation; D053612:Janus Kinases / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D064067:Rho Guanine Nucleotide Exchange Factors / Q000276:immunology; D020837:SOS1 Protein / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C576600:ARHGEF1 protein, human; C551174:ARHGEF28 protein, human; D018925:Chemokines; C402110:DOCK2 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D016169:Lymphocyte Function-Associated Antigen-1; D064067:Rho Guanine Nucleotide Exchange Factors; D020837:SOS1 Protein; D053612:Janus Kinases