c‐Abl tyrosine kinase plays a critical role in β2 integrin‐dependent neutrophil migration by regulating Vav1 activity

[摘要] Therecruitmentandmigrationofneutrophilsarecriticalforinnateimmunityandacuteinflammatoryresponses.However,themechanismthatregulatestherecruitmentandmigrationofneutrophilshasnotbeenwellcharacterized.Wehererevealanovelfunctionofc‐Ablkinaseinregulatingneutrophilmigration.Ourresultsdemonstratethatc‐Ablkinaseisrequiredforneutrophilrecruitmentinvivoandmigrationinvitro,andtheinhibitionofc‐Ablkinaseactivityhasasignificantimpactonneutrophilmigratorybehavior.Moreover,c‐Ablkinaseactivationdependsonβ2integrinengagement,andtheactivatedc‐Ablkinasefurtherregulatesactinpolymerizationandmembraneprotrusiondynamicsattheextendedleadingedgesduringneutrophilmigration.Inaddition,weidentifytheRhoGEFVav1asamajordownstreameffectorofc‐Ablkinase.TheC‐terminalSH3‐SH2‐SH3domainandproline‐richregionofVav1arerequiredforitsinteractionwithc‐Ablkinase,andc‐AblkinaseprobablyregulatestheactivityofVav1bydirectphosphorylationatTyr‐267intheDHdomain.Together,theseresultsindicatethatc‐Ablkinaseplaysacriticalroleinβ2integrin‐dependentneutrophilmigrationbyregulatingVav1activity...

[学科分类] 生理学

[关键词] membrane protrusion;HL‐60;F‐actin;acute inflammation;PMNs;cytoskeletal rearrangement