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; Jim C. Norman

doi:10.1038/ncomms14646

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, Jim C. Norman

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	14646
Journal	Nature Communications
Volume	8
Early online date	15 Mar 2017
DOIs	https://doi.org/10.1038/ncomms14646
Publication status	Published - 2017

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Gundry, C., Marco, S., Rainero, E., Miller, B., Dornier, E., Mitchell, L., Caswell, P. T., Campbell, A. D., Hogeweg, A., Sansom, O. J., Morton, J. P., & Norman, J. C. (2017). Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell: cell repulsion. Nature Communications, 8, Article 14646. Advance online publication. https://doi.org/10.1038/ncomms14646

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

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.",

author = "Christine Gundry and Sergi Marco and Elena Rainero and Bryan Miller and Emmanuel Dornier and Louise Mitchell and Caswell, {Patrick T.} and Campbell, {Andrew D.} and Anna Hogeweg and Sansom, {Owen J.} and Morton, {Jennifer P.} and Norman, {Jim C.}",

year = "2017",

doi = "10.1038/ncomms14646",

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T2 - cell repulsion

AU - Gundry, Christine

AU - Marco, Sergi

AU - Rainero, Elena

AU - Miller, Bryan

AU - Dornier, Emmanuel

AU - Mitchell, Louise

AU - Caswell, Patrick T.

AU - Campbell, Andrew D.

AU - Hogeweg, Anna

AU - Sansom, Owen J.

AU - Morton, Jennifer P.

AU - Norman, Jim C.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

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VL - 8

JO - Nature Communications

JF - Nature Communications

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ER -

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

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