title: DAPK2 positively regulates motility of neutrophils and eosinophils in response to intermediary chemoattractants.
abstract: The tight regulation of granulocyte chemotaxis is crucial for initiation and resolution of inflammation. Here, we show that DAPK2, a Ca(2+)/CaM-sensitive serine/threonine kinase known to modulate cell death in various cell types, is a novel regulator of migration in granulocytes. We demonstrate that human neutrophils and eosinophils express DAPK2 but unlike other leukocytes, no DAPK1 or DAPK3 protein. When DAPK activities were blocked by inhibitors, we found that neither granulocyte lifespan nor phagocytosis was affected. However, such pharmacological inactivation of DAPK activity abolished motility of granulocytes in response to intermediary but not end-target chemoattractants ex vivo. The defect in chemotaxis in DAPK2-inactive granulocytes is likely a result of reduced polarization of the cells, mediated by a lack of MLC phosphorylation, resulting in radial F-actin and pseudopod formation. As neutrophils treated with DAPKi also showed reduced recruitment to the site of inflammation in a mouse peritonitis model, DAPK2 may be a novel target for anti-inflammatory therapies.
authors.affiliation: 2.University of Bern, Friedbuehlstrasse 49, CH-3010 Bern, Switzerland. hus@pki.unibe.ch.
authors.forename: Barbara
authors.initials: B
authors.lastname: Geering
authors.forename: Christina
authors.initials: C
authors.lastname: Stoeckle
authors.forename: Sasa
authors.initials: S
authors.lastname: Rozman
authors.forename: Kevin
authors.initials: K
authors.lastname: Oberson
authors.forename: Charaf
authors.initials: C
authors.lastname: Benarafa
authors.forename: Hans-Uwe
authors.initials: HU
authors.lastname: Simon
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology*; D064550:Death-Associated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D019169:Jurkat Cells; D051379:Mice; D018994:Myosin Light Chains / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010538:Peritonitis / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D002630:Chemotactic Factors; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases; C579103:dapk2 protein, mouse
keywords: death-associated protein kinase; granulocyte; inflammation; inhibitor; migration