title: GPCR-mediated PLCβγ/PKCβ/PKD signaling pathway regulates the cofilin phosphatase slingshot 2 in neutrophil chemotaxis.
abstract: Chemotaxis requires precisely coordinated polymerization and depolymerization of the actin cytoskeleton at leading fronts of migrating cells. However, GPCR activation-controlled F-actin depolymerization remains largely elusive. Here, we reveal a novel signaling pathway, including Gαi, PLC, PKCβ, protein kinase D (PKD), and SSH2, in control of cofilin phosphorylation and actin cytoskeletal reorganization, which is essential for neutrophil chemotaxis. We show that PKD is essential for neutrophil chemotaxis and that GPCR-mediated PKD activation depends on PLC/PKC signaling. More importantly, we discover that GPCR activation recruits/activates PLCγ2 in a PI3K-dependent manner. We further verify that PKCβ specifically interacts with PKD1 and is required for chemotaxis. Finally, we identify slingshot 2 (SSH2), a phosphatase of cofilin (actin depolymerization factor), as a target of PKD1 that regulates cofilin phosphorylation and remodeling of the actin cytoskeleton during neutrophil chemotaxis.
authors.affiliation: Chemotaxis Signaling Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Xu
authors.affiliation: Chemotaxis Signaling Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gera
authors.affiliation: Chemotaxis Signaling Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852 Center of Therapeutic Research for Hepatocellular Carcinoma, 302 Hospital of PLA, Beijing 100039, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Chemotaxis Signaling Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Michelle
authors.initials: M
authors.lastname: Yun
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Chemotaxis Signaling Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Q Jane
authors.initials: QJ
authors.lastname: Wang
authors.affiliation: Chemotaxis Signaling Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Tian
authors.initials: T
authors.lastname: Jin
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D051338:Cofilin 1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D054799:Phospholipase C beta / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D051338:Cofilin 1; D043562:Receptors, G-Protein-Coupled; C089212:protein kinase D; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D010749:Phosphoprotein Phosphatases; C525231:slingshot phosphatase 2, human; D054799:Phospholipase C beta; D051966:Phospholipase C gamma