title: The Mammalian Sterile 20-like 1 Kinase Controls Selective CCR7-Dependent Functions in Human Dendritic Cells.
abstract: The chemokine receptor CCR7 directs mature dendritic cells (mDCs) to the lymph nodes where these cells control the initiation of the immune response. CCR7 regulates chemotaxis, endocytosis, survival, migratory speed, and cytoarchitecture in mDCs. The molecular mechanisms used by CCR7 to regulate these functions in mDCs are not completely understood. The mammalian sterile 20-like 1 kinase (Mst1) plays a proapoptotic role under stress conditions; however, recently, it has been shown that Mst1 can also control homeostatic cell functions under normal conditions. In this study, we show that stimulation of CCR7 in mDCs induces Gαi-dependent activation of Mst1, suggesting the involvement of this kinase in the control of CCR7-dependent functions. Analysis of the mDCs in which Mst1 expression levels were reduced with small interfering RNA shows that this kinase mediates CCR7-dependent effects on cytoarchitecture, endocytosis and migratory speed but not on chemotaxis or survival. In line with these results, biochemical analysis indicates that Mst1 does not control key signaling regulators of CCR7-dependent chemotaxis or survival. In contrast, Mst1 regulates downstream of CCR7 and, of note, independently of Gα13, the RhoA pathway. Reduction of Mst1 inhibits CCR7-dependent phosphorylation of downstream targets of RhoA, including cofilin, myosin L chain, and myosin L chain phosphatase. Consistent with the role of the latter molecules as modulators of the actin cytoskeleton, mDCs with reduced Mst1 also displayed a dramatic reduction in actin barbed-end formation that could not be recovered by stimulating CCR7. The results indicate that the kinase Mst1 controls selective CCR7-dependent functions in human mDCs.
authors.affiliation: Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; and.
authors.forename: Jesús
authors.initials: J
authors.lastname: Torres-Bacete
authors.affiliation: Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Delgado-Martín
authors.affiliation: Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; and.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gómez-Moreira
authors.affiliation: Chemical Biology Department, RIKEN Advanced Science Institute, 230-0045 Kanagawa, Japan.
authors.forename: Siro
authors.initials: S
authors.lastname: Simizu
authors.affiliation: Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; and rodrifer@cib.csic.es.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Rodríguez-Fernández
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002633:Chemotaxis / Q000235:genetics; D051338:Cofilin 1 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004705:Endocytosis / Q000235:genetics; D004789:Enzyme Activation; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008198:Lymph Nodes / Q000276:immunology; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D054400:Receptors, CCR7 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D051338:Cofilin 1; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D047908:Intracellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; D009219:Myosin-Light-Chain Kinase; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D054400:Receptors, CCR7; D020742:rhoA GTP-Binding Protein; C515370:CCR7 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases