Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior

  1. Rochelle Shirin Sadeghi
  2. Katarzyna Kulej
  3. Rahul Singh Kathayat
  4. Benjamin A Garcia
  5. Bryan C Dickinson
  6. Donita C Brady  Is a corresponding author
  7. Eric Witze  Is a corresponding author
  1. University of Pennsylvania, United States
  2. University of Chicago, United States

Abstract

Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remain unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity. We found phosphorylation increased APT1 depalmitoylating activity and reduced APT1 dimerization. We further determined APT1 phosphorylation increases melanoma invasion in vitro, and also correlated with increased tumor grade and metastasis. Our results further establish APT1 as an important regulator of melanoma invasion and metastatic behavior. Inhibition of APT1 may represent a novel way to treat Wnt5a driven cancers.

Data availability

All MS-APT1 raw files have been deposited in the CHORUS database under project number 1456 (https://chorusproject.org/).

Article and author information

Author details

  1. Rochelle Shirin Sadeghi

    Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  2. Katarzyna Kulej

    Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  3. Rahul Singh Kathayat

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    Rahul Singh Kathayat, has applied for a provisional patent for DPP-3. A patent number has not been assigned.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9159-2413
  4. Benjamin A Garcia

    Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  5. Bryan C Dickinson

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    Bryan C Dickinson, has applied for a provisional patent for DPP-3. A patent number has not been assigned.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9616-1911
  6. Donita C Brady

    Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    bradyd@pennmedicine.upenn.edu
    Competing interests
    No competing interests declared.
  7. Eric Witze

    Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    ewitze@upenn.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7699-4879

Funding

National Cancer Institute (CA181633)

  • Eric Witze

American Cancer Society (RSG-15-027-01)

  • Eric Witze

National Institute of Allergy and Infectious Diseases (AI118891)

  • Benjamin A Garcia

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

Reviewing Editor

  1. William I Weis, Stanford University Medical Center, United States

Publication history

  1. Received: December 14, 2017
  2. Accepted: April 11, 2018
  3. Accepted Manuscript published: April 12, 2018 (version 1)
  4. Version of Record published: April 26, 2018 (version 2)

Copyright

© 2018, Sadeghi 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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  1. Rochelle Shirin Sadeghi
  2. Katarzyna Kulej
  3. Rahul Singh Kathayat
  4. Benjamin A Garcia
  5. Bryan C Dickinson
  6. Donita C Brady
  7. Eric Witze
(2018)
Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior
eLife 7:e34362.
https://doi.org/10.7554/eLife.34362

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