The sphingosine 1-phosphate receptor 2 is shed in exosomes from breast cancer cells and is N-terminally processed to a short constitutively active form that promotes extracellular signal regulated kinase activation and DNA synthesis in fibroblasts
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Ashref El Buri1, David R. Adams2, Douglas Smith1, Rothwelle J. Tate1, Margaret Mullin3, Susan Pyne1 and Nigel J. Pyne1
1Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK
2School of Engineering & Physical Sciences, Heriot-Watt University, Edinburgh, Scotland, UK
3Electron Microscopy Facility, School of Life Sciences, MVLS, Joseph Black Building, University of Glasgow, Glasgow, Scotland, UK
Nigel J. Pyne, email: [email protected]
Keywords: sphingosine 1-phosphate; sphingosine 1-phosphate receptors; exosomes; fibroblasts; cancer
Received: May 07, 2018 Accepted: June 04, 2018 Published: June 29, 2018
We demonstrate here that the G protein-coupled receptor (GPCR), sphingosine 1-phosphate receptor 2 (S1P2, Mr = 40 kDa) is shed in hsp70+ and CD63+ containing exosomes from MDA-MB-231 breast cancer cells. The receptor is taken up by fibroblasts, where it is N-terminally processed to a shorter form (Mr = 36 kDa) that appears to be constitutively active and able to stimulate the extracellular signal regulated kinase-1/2 (ERK-1/2) pathway and DNA synthesis. An N-terminally truncated construct of S1P2, which may correspond to the processed form of the receptor generated in fibroblasts, was found to be constitutively active when over-expressed in HEK293 cells. Analysis based on the available crystal structure of the homologous S1P1 receptor suggests that, in the inactive-state, the N-terminus of S1P2 may tension TM1 so as to maintain a compressive action on TM7. This in turn may stabilise a closed basal state interface between the intracellular ends of TM7 and TM6. Cleavage and removal of the S1P2 N-terminal peptide is postulated to facilitate relaxation of TM1 and accompanying separation of TM6 and TM7. The latter transition is one of the key elements of G protein engagement and is required to open the intracellular coupling interface beneath the GPCR helix bundle. Therefore, removal at the N-terminus of S1P2 is likely to enhance G protein coupling. These findings provide the first evidence that S1P2 is released from breast cancer cells in exosomes and is processed by fibroblasts to promote ERK signaling and proliferation of these cells.
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