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

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 and Jim C. Norman ()
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Christine Gundry: CRUK Beatson Institute for Cancer Research, Garscube Estate
Sergi Marco: CRUK Beatson Institute for Cancer Research, Garscube Estate
Elena Rainero: CRUK Beatson Institute for Cancer Research, Garscube Estate
Bryan Miller: CRUK Beatson Institute for Cancer Research, Garscube Estate
Emmanuel Dornier: CRUK Beatson Institute for Cancer Research, Garscube Estate
Louise Mitchell: CRUK Beatson Institute for Cancer Research, Garscube Estate
Patrick T. Caswell: CRUK Beatson Institute for Cancer Research, Garscube Estate
Andrew D. Campbell: CRUK Beatson Institute for Cancer Research, Garscube Estate
Anna Hogeweg: CRUK Beatson Institute for Cancer Research, Garscube Estate
Owen J. Sansom: CRUK Beatson Institute for Cancer Research, Garscube Estate
Jennifer P. Morton: CRUK Beatson Institute for Cancer Research, Garscube Estate
Jim C. Norman: CRUK Beatson Institute for Cancer Research, Garscube Estate

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14646

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