title: A PLCβ/PI3Kγ-GSK3 signaling pathway regulates cofilin phosphatase slingshot2 and neutrophil polarization and chemotaxis.
abstract: Neutrophils, in response to a chemoattractant gradient, undergo dynamic F-actin remodeling, a process important for their directional migration or chemotaxis. However, signaling mechanisms for chemoattractants to regulate the process are incompletely understood. Here, we characterized chemoattractant-activated signaling mechanisms that regulate cofilin dephosphorylation and actin cytoskeleton reorganization and are critical for neutrophil polarization and chemotaxis. In neutrophils, chemoattractants induced phosphorylation and inhibition of GSK3 via both PLCβ-PKC and PI3Kγ-AKT pathways, leading to the attenuation of GSK3-mediated phosphorylation and inhibition of the cofilin phosphatase slingshot2 and an increase in dephosphorylated, active cofilin. The relative contribution of this GSK3-mediated pathway to neutrophil chemotaxis regulation depended on neutrophil polarity preset by integrin-induced polarization of PIP5K1C. Therefore, our study characterizes a signaling mechanism for chemoattractant-induced actin cytoskeleton remodeling and elucidates its context-dependent role in regulating neutrophil polarization and chemotaxis.
authors.affiliation: Department of Pharmacology and Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Tang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Xu
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.forename: John
authors.initials: J
authors.lastname: Sondek
authors.forename: Le
authors.initials: L
authors.lastname: Sun
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002465:Cell Movement / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000502:physiology*; D054799:Phospholipase C beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D016023:Integrins; D034741:RNA, Small Interfering; D017853:Phosphotransferases (Alcohol Group Acceptor); D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D054799:Phospholipase C beta