期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 101, 期 1, 页码 239-251出版社
WILEY
DOI: 10.1189/jlb.2A1215-572R
关键词
GPCR; cell migration; GTPase
资金
- Intramural Research Program of the U.S. National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases [AI001156]
- NIH National Heart, Lung, and Blood Institute [R01-HL116327]
beta-Arrestins have emerged as key regulators of cytoskeletal rearrangement that are required for directed cell migration. Whereas it is known that beta-arrestins are required for formyl-Met-Leu-Phe receptor (FPR) recycling, less is known about their role in regulating FPR-mediated neutrophil chemotaxis. Here, we show that beta-arrestin 1 (ArrB1) coaccumulated with F-actin within the leading edge of neutrophil-like HL-60 cells during chemotaxis, and its knockdown resulted in markedly reduced migration within fMLP gradients. The small GTPase Ras-related protein 2 (Rap2) was found to bind ArrB1 under resting conditions but dissociated upon fMLP stimulation. The FPR-dependent activation of Rap2 required ArrB1 but was independent of G alpha(i) activity. Significantly, depletion of either ArrB1 or Rap2 resulted in reduced chemotaxis and defects in cellular repolarization within fMLP gradients. These data strongly suggest a model in which FPR is able to direct ArrB1 and other bound proteins that are required for lamellipodial extension to the leading edge in migrating neutrophils, thereby orientating and directing cell migration.
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