Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28294115.
- Also identified by DOI 10.1038/ncomms14646 and PMC identifier 5355957.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>435</sup> by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser<sup>897</sup> 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.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Membrane Proteins
- Protein Serine-Threonine Kinases
- Receptor, EphA2
- rab GTP-Binding Proteins