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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 Ser 435  by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser 897  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 .

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