TY - JOUR
T1 - β-arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6
AU - Borroni, Elena M.
AU - Cancellieri, Cinzia
AU - Vacchini, Alessandro
AU - Benureau, Yann
AU - Lagane, Bernard
AU - Bachelerie, Françoise
AU - Arenzana-Seisdedos, Fernando
AU - Mizuno, Kensaku
AU - Mantovani, Alberto
AU - Bonecchi, Raffaella
AU - Locati, Massimo
PY - 2013/4/30
Y1 - 2013/4/30
N2 - 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 b-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.
AB - 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 b-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.
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U2 - 10.1126/scisignal.2003627
DO - 10.1126/scisignal.2003627
M3 - Article
AN - SCOPUS:84877591484
VL - 6
JO - Science Signaling
JF - Science Signaling
SN - 1937-9145
IS - 273
ER -