Eph receptor tyrosine kinases and their ligands ephrins are involved in many physiological processes, including tissue homeostasis, vascularisation and development. They are also involved in promoting angiogenesis and metastasis in many cancers, including breast, colon and lung. Upon interaction with EphB receptors, ephrinB ligands signal through SH2- and PDZ-interacting cytoplasmic adaptors. To date, little is known on PDZ-mediated ephrinB signalling. The aim of our study was to determine the role of PDZ domain-containing proteins in modulating ephrinB2 signalling and trafficking pathways in the context of epithelial breast cancer cells, with a specific focus on the scaffolding protein syntenin-1. We also endeavoured to determine whether the ephrinB2 – syntenin-1 axis affects breast cancer tumourigenesis. Our findings demonstrate that syntenin-1 modulates ephrinB2 internalization upon receptor-induced stimulation and that this affects ephrinB signalling. Furthermore, we found that phospho-Tyr330 on ephrinB2 increases binding to the PDZ domain-containing proteins syntenin-1 and PAR3. Finally, we report that ephrinB2 drives MCF7 colony growth in 3D cultures and that syntenin-1 is involved in boundary formation between ephrinB2 and EphB4 expressing cells. These findings describe, for the first time, the role of syntenin-1 in ephrinB2 signalling and the functional relevance of the ephrinB2 – syntenin-1 axis in epithelial breast cancer pathways.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:607223 |
| Date | January 2014 |
| Creators | Parks, Michael |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/5062/ |
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