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AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network

Author

Listed:
  • Afnan Abu-Thuraia

    (Montreal Clinical Research Institute (IRCM)
    Université de Montréal)

  • Marie-Anne Goyette

    (Montreal Clinical Research Institute (IRCM)
    Université de Montréal)

  • Jonathan Boulais

    (Montreal Clinical Research Institute (IRCM))

  • Carine Delliaux

    (Montreal Clinical Research Institute (IRCM))

  • Chloé Apcher

    (Montreal Clinical Research Institute (IRCM)
    Université de Montréal)

  • Céline Schott

    (Montreal Clinical Research Institute (IRCM)
    Université de Montréal)

  • Rony Chidiac

    (Université de Montréal)

  • Halil Bagci

    (Montreal Clinical Research Institute (IRCM)
    McGill University
    ETH Zürich)

  • Marie-Pier Thibault

    (Montreal Clinical Research Institute (IRCM))

  • Dominique Davidson

    (Montreal Clinical Research Institute (IRCM))

  • Mathieu Ferron

    (Montreal Clinical Research Institute (IRCM)
    Université de Montréal
    McGill University)

  • André Veillette

    (Montreal Clinical Research Institute (IRCM)
    Université de Montréal)

  • Roger J. Daly

    (Monash University)

  • Anne-Claude Gingras

    (Sinai Health System
    University of Toronto)

  • Jean-Philippe Gratton

    (Université de Montréal)

  • Jean-François Côté

    (Montreal Clinical Research Institute (IRCM)
    Université de Montréal
    McGill University
    Université de Montréal)

Abstract

Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins, culminating in faster FA disassembly. Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.

Suggested Citation

  • Afnan Abu-Thuraia & Marie-Anne Goyette & Jonathan Boulais & Carine Delliaux & Chloé Apcher & Céline Schott & Rony Chidiac & Halil Bagci & Marie-Pier Thibault & Dominique Davidson & Mathieu Ferron & An, 2020. "AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17415-x
    DOI: 10.1038/s41467-020-17415-x
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    Cited by:

    1. Guillaume Serwe & David Kachaner & Jessica Gagnon & Cédric Plutoni & Driss Lajoie & Eloïse Duramé & Malha Sahmi & Damien Garrido & Martin Lefrançois & Geneviève Arseneault & Marc K. Saba-El-Leil & Syl, 2023. "CNK2 promotes cancer cell motility by mediating ARF6 activation downstream of AXL signalling," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Le Yu & Yu Deng & Xiaodong Wang & Charlene Santos & Ian J. Davis & H. Shelton Earp & Pengda Liu, 2024. "Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Josefine Radke & Elisa Schumann & Julia Onken & Randi Koll & Güliz Acker & Bohdan Bodnar & Carolin Senger & Sascha Tierling & Markus Möbs & Peter Vajkoczy & Anna Vidal & Sandra Högler & Petra Kodajova, 2022. "Decoding molecular programs in melanoma brain metastases," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    4. Michael J. Roy & Minglyanna G. Surudoi & Ashleigh Kropp & Jianmei Hou & Weiwen Dai & Joshua M. Hardy & Lung-Yu Liang & Thomas R. Cotton & Bernhard C. Lechtenberg & Toby A. Dite & Xiuquan Ma & Roger J., 2023. "Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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