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)

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 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.)
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Norman, Professor James and Mitchell, Mrs Louise and Dornier, Mr Emmanuel Greg and Caswell, Dr Patrick and Rainero, Ms Elena and Morton, Professor Jen 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 Publishing Group
• ISSN: 2041-1723
• 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