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Diversification of TAM receptor tyrosine kinase function

Nature Immunology volume 15, pages 920928 (2014) | Download Citation

Abstract

The clearance of apoptotic cells is critical for both tissue homeostasis and the resolution of inflammation. We found that the TAM receptor tyrosine kinases Axl and Mer had distinct roles as phagocytic receptors in these two settings, in which they exhibited divergent expression, regulation and activity. Mer acted as a tolerogenic receptor in resting macrophages and during immunosuppression. In contrast, Axl was an inflammatory response receptor whose expression was induced by proinflammatory stimuli. Axl and Mer differed in their ligand specificities, ligand-receptor complex formation in tissues, and receptor shedding upon activation. These differences notwithstanding, phagocytosis by either protein was strictly dependent on receptor activation triggered by bridging of TAM receptor–ligand complexes to the 'eat-me' signal phosphatidylserine on the surface of apoptotic cells.

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Acknowledgements

We thank M. Joens and J. Fitzpatrick for processing samples and acquiring scanning electron microscopic images; R. Evans (Salk Institute) for nuclear receptor agonists T0901317, GW501516 and BRL49653; J. Hash, P. Burrola and C. Mayer for technical support; and members of the Lemke laboratory and the Nomis Center for discussions. Supported by the US National Institutes of Health (R01 AI077058, R01 AI101400 and R01 NS085296 to G.L.), the Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002 to G.L.) the Nomis Foundation, the H.N. and Frances C. Berger Foundation, the Fritz B. Burns Foundation, the HKT Foundation, Françoise Gilot-Salk, the Human Frontiers Science Program (A.Z.), the Marie Curie Seventh Framework Programme (P.G.T.), the Leukemia and Lymphoma Society and the Nomis Foundation (E.D.L.).

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Affiliations

  1. Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Anna Zagórska
    • , Paqui G Través
    • , Erin D Lew
    •  & Greg Lemke
  2. MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.

    • Ian Dransfield
  3. Immunobiology and Microbial Pathogenesis Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Greg Lemke

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Contributions

A.Z. designed and performed the experiments; P.G.T. aided in the design and execution of in vivo experiments; E.D.L. prepared purified recombinant GAS-6; I.D. aided in the design of the flow-cytometry-based phagocytosis assay; G.L. contributed to the design of the experiments and wrote the manuscript.

Competing interests

G.L. is a shareholder in Kolltan Pharmaceuticals.

Corresponding author

Correspondence to Greg Lemke.

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DOI

https://doi.org/10.1038/ni.2986

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