title: β-arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6.
abstract: Chemokines promote the recruitment of leukocytes to sites of infection and inflammation by activating conventional heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). Chemokines are also recognized by a set of atypical chemokine receptors (ACRs), which cannot induce directional cell migration but are required for the generation of chemokine gradients in tissues. ACRs are presently considered "silent receptors" because no G protein-dependent signaling activity is observed after their engagement by cognate ligands. We report that engagement of the ACR D6 by its ligands activates a β-arrestin1-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin through the Rac1-p21-activated kinase 1 (PAK1)-LIM kinase 1 (LIMK1) cascade. This signaling pathway is required for the increased abundance of D6 protein at the cell surface and for its chemokine-scavenging activity. We conclude that D6 is a signaling receptor that exerts its regulatory function on chemokine-mediated responses in inflammation and immunity through a distinct signaling pathway.
authors: Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20089 Rozzano, Milan, Italy.
authors: Elena M
authors: EM
authors: Borroni
authors: Cinzia
authors: C
authors: Cancellieri
authors: Alessandro
authors: A
authors: Vacchini
authors: Yann
authors: Y
authors: Benureau
authors: Bernard
authors: B
authors: Lagane
authors: Françoise
authors: F
authors: Bachelerie
authors: Fernando
authors: F
authors: Arenzana-Seisdedos
authors: Kensaku
authors: K
authors: Mizuno
authors: Alberto
authors: A
authors: Mantovani
authors: Raffaella
authors: R
authors: Bonecchi
authors: Massimo
authors: M
authors: Locati
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism; D054447:Receptors, CCR10 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071557:beta-Arrestins; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D000097628:Chemokine Receptor D6
chemical_list: D051339:Actin Depolymerizing Factors; D019390:Arrestins; D054461:Lim Kinases; D054447:Receptors, CCR10; D000071557:beta-Arrestins; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D000097628:Chemokine Receptor D6; C107953:RAC1 protein, human; C515892:LIMK1 protein, human; C515903:PAK1 protein, human