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

Gundry, C. et al. (2017) Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion. Nature Communications, 8, 14646. (doi: 10.1038/ncomms14646) (PMID:28294115) (PMCID:PMC5355957)

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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.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK-grant number; JCN, C596/A18277, and Breast Cancer Now (to support E.D.)
Glasgow Author(s) Enlighten ID:Norman, Professor James and Caswell, Dr Patrick and Mitchell, Mrs Louise and Rainero, Ms Elena and Morton, Professor Jen and Dornier, Mr Emmanuel Greg and Sansom, Professor Owen and Campbell, Dr Andrew
Authors: Gundry, C., Marco, S., Rainero, E., Miller, B., Dornier, E., Mitchell, L., Caswell, P. T., Campbell, A., Hogeweg, A., Sansom, O. J., Morton, J. P., and Norman, J. C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Research
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Nature Communications 8: 14646
Publisher Policy:Reproduced under a Creative Commons License

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