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 Ser435by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser897by 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.
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Gundry
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Sergi
authors.initials: S
authors.lastname: Marco
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Rainero
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Miller
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dornier
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Mitchell
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.|Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Patrick T
authors.identifier: 0000-0002-2633-2324
authors.initials: PT
authors.lastname: Caswell
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Hogeweg
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Owen J
authors.identifier: 0000-0001-9540-3010
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.affiliation: CRUK Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D055786:Gene Knockout Techniques; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D040901:Proteomics; D036104:Receptor, EphA2 / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C488966:RAB11FIP1 protein, human; D010768:Phosphoserine; D017228:Hepatocyte Growth Factor; D036104:Receptor, EphA2; C560359:LMTK3 protein, human; D017346:Protein Serine-Threonine Kinases; C553411:Rab14 protein, human; D020691:rab GTP-Binding Proteins