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Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion

Author

Listed:
  • Christine Gundry

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Sergi Marco

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Elena Rainero

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Bryan Miller

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Emmanuel Dornier

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Louise Mitchell

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Patrick T. Caswell

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow
    Cell-Matrix Research, Faculty of Life Sciences, University of Manchester)

  • Andrew D. Campbell

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Anna Hogeweg

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Owen J. Sansom

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Jennifer P. Morton

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

  • Jim C. Norman

    (CRUK Beatson Institute for Cancer Research, Garscube Estate
    Institute of Cancer Sciences, University of Glasgow)

Abstract

The Rab GTPase effector, Rab-coupling protein (RCP) is known to promote invasive behaviour in vitro by controlling integrin and receptor tyrosine kinase (RTK) trafficking, but how RCP influences metastasis in vivo is unclear. Here we identify an RTK of the Eph family, EphA2, to be a cargo of an RCP-regulated endocytic pathway which controls cell:cell repulsion and metastasis in vivo. Phosphorylation of RCP at Ser435 by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser897 by Akt are both necessary to promote Rab14-dependent (and Rab11-independent) trafficking of EphA2 which generates cell:cell repulsion events that drive tumour cells apart. Genetic disruption of RCP or EphA2 opposes cell:cell repulsion and metastasis in an autochthonous mouse model of pancreatic adenocarcinoma—whereas conditional knockout of another RCP cargo, α5 integrin, does not suppress pancreatic cancer metastasis—indicating a role for RCP-dependent trafficking of an Eph receptor to drive tumour dissemination in vivo.

Suggested Citation

  • Christine Gundry & Sergi Marco & Elena Rainero & Bryan Miller & Emmanuel Dornier & Louise Mitchell & Patrick T. Caswell & Andrew D. Campbell & Anna Hogeweg & Owen J. Sansom & Jennifer P. Morton & Jim , 2017. "Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14646
    DOI: 10.1038/ncomms14646
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