1. Biochemistry and Chemical Biology
  2. Cell Biology
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DPP9 is a novel component of the N-end rule pathway targeting the Tyrosine Kinase Syk

  1. Daniela Justa-Schuch
  2. Maria Silva-Garcia
  3. Esther Pilla
  4. Michael Engelke
  5. Markus Kilisch
  6. Christof Lenz
  7. Ulrike Möller
  8. Fumihiko Nakamura
  9. Henning Urlaub
  10. Ruth Geiss-Friedlander  Is a corresponding author
  1. University Medical Center Goettingen, Germany
  2. MRC Laboratory of Molecular Biology, United Kingdom
  3. Harvard Medical School, United States
Research Article
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Cite this article as: eLife 2016;5:e16370 doi: 10.7554/eLife.16370

Abstract

The aminopeptidase DPP9 removes dipeptides from N-termini of substrates having a proline or alanine in second position. Although linked to several pathways including cell survival and metabolism, the molecular mechanisms underlying these outcomes are poorly understood. We identified a novel interaction of DPP9 with Filamin A, which recruits DPP9 to Syk, a central kinase in B-cell signalling. Syk signalling can be terminated by degradation, requiring the ubiquitin E3 ligase Cbl. We show that DPP9 cleaves Syk to produce a neo N-terminus with serine in position 1. Pulse-chases combined with mutagenesis studies reveal that Ser1 strongly influences Syk stability. Furthermore, DPP9 silencing reduces Cbl interaction with Syk, suggesting that DPP9 processing is a prerequisite for Syk ubiquitination. Consistently, DPP9 inhibition stabilizes Syk, thereby modulating Syk signalling. Taken together, we demonstrate DPP9 as a negative regulator of Syk and conclude that DPP9 is a novel integral aminopeptidase of the N-end rule pathway.

Article and author information

Author details

  1. Daniela Justa-Schuch

    Department of Molecular Biology, University Medical Center Goettingen, Goettingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Maria Silva-Garcia

    Department of Molecular Biology, University Medical Center Goettingen, Goettingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Esther Pilla

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael Engelke

    Institute of Cellular and Molecular Immunology, University Medical Center Goettingen, Goettingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Markus Kilisch

    Department of Molecular Biology, University Medical Center Goettingen, Goettingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Christof Lenz

    Bioanalytics, Institute of Clinical Chemistry, University Medical Center Goettingen, Goettingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0946-8166
  7. Ulrike Möller

    Department of Molecular Biology, University Medical Center Goettingen, Goettingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Fumihiko Nakamura

    Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Henning Urlaub

    Bioanalytics, Institute of Clinical Chemistry, University Medical Center Goettingen, Goettingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Ruth Geiss-Friedlander

    Department of Molecular Biology, University Medical Center Goettingen, Goettingen, Germany
    For correspondence
    rgeiss@gwdg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1720-3440

Funding

Deutsche Forschungsgemeinschaft (2234/1-2)

  • Ruth Geiss-Friedlander

Heidenreich von Siebold-Programm, Universitaetsmedizin Goettingen

  • Ruth Geiss-Friedlander

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Matthew Freeman, University of Oxford, United Kingdom

Publication history

  1. Received: March 24, 2016
  2. Accepted: September 7, 2016
  3. Accepted Manuscript published: September 10, 2016 (version 1)
  4. Version of Record published: September 27, 2016 (version 2)

Copyright

© 2016, Justa-Schuch et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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