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Regulation of tyrosine kinase activation and granule release through β-arrestin by CXCR1

Nature Immunology volume 1, pages 227–233 (2000)Cite this article

Abstract

Chemoattractant-stimulated granule release from neutrophils, basophils and eosinophils is critical for the innate immune response against infectious bacteria. Interleukin 8 (IL-8) activation of the chemokine receptor CXCR1 was found to stimulate rapid formation of β-arrestin complexes with Hck or c-Fgr. Formation of β-arrestin–Hck complexes led to Hck activation and trafficking of the complexes to granule-rich regions. Granulocytes expressing a dominant-negative β-arrestin–mutant did not release granules or activate tyrosine kinases after IL-8 stimulation. Thus, β-arrestins regulate chemokine-induced granule exocytosis, indicating a broader role for β-arrestins in the regulation of cellular functions than was previously suspected.

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Figure 1: PP1 blocks degranulation and β-arrestin interacts with Hck in IL-8–stimulated neutrophils.
Figure 2: Dominant-negative β-arrestin 1 P91G-P121E mutant blocks N-acetyl-d-glucosaminidase release and tyrosine phosphorylation.
Figure 3: 4STm-CXCR1 and 8STm-CXCR1 block IL-8–induced degranulation.
Figure 4: Active Hck relocalizes to the areas of granule fusion in RBL-2H3 cells expressing CXCR1 in response to IL-8.
Figure 5: β-arrestin localizes to granules.
Figure 6: Model of β-arrestin–regulated granule release.

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Acknowledgements

We thank A. Leaist and S. Zawada for technical assistance, and G. Downey for comments on the manuscript. Supported by grants from the Medical Research Council of Canada (to D.J.K., R.D.F and S.S.G.F.), the Medical Research Council-Juvenile Diabetes Foundation International (to D.J.K.), the Heart and Stroke Foundation of Canada (to D.J.K., R.D.F. and S.S.G.F.) and Premiers Research Excellence Award (to D.J.K.). D.J.K. is a Medical Research Council of Canada scholar. S.S.G.F. is a Heart and Stroke Foundation of Canada scholar.

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Author notes

  1. Joseph D. Andrews and Alyson A. Kelvin: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Immunology and Inflammation, John P. Robarts Research Institute, 1400 Western Road, London, N6G 2V4, Ontario, Canada

    Jana Barlic, Joseph D. Andrews, Alyson A. Kelvin, Steven E. Bosinger, Mark E. DeVries, Luoling Xu & David J. Kelvin

  2. Department of Microbiology and Immunology, University of Western Ontario, London, N6A 5C1, Ontario, Canada

    Jana Barlic, Steven E. Bosinger, Mark E. DeVries & David J. Kelvin

  3. Neurodegenerative Diseases Group, John P. Robarts Research Institute, 100 Perth Drive, London, N6G 5K8, Ontario, Canada

    Tomas Dobransky

  4. Departments of Medicine, Physiology, Pharmacology and Toxicology, The University of Western Ontario, and John P. Robarts Research Institute, London, N6A 5K8, Ontario, Canada

    Ross D. Feldman & Stephen S. G. Ferguson

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Barlic, J., Andrews, J., Kelvin, A. et al. Regulation of tyrosine kinase activation and granule release through β-arrestin by CXCR1. Nat Immunol 1, 227–233 (2000). https://doi.org/10.1038/79767

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