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Published 24 April 2006. doi:10.1083/jcb.200506033
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 2, 301-310
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Article

 Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1

Olga Sukocheva1, Carol Wadham1, Andrew Holmes1, Nathaniel Albanese1, Emily Verrier1, Feng Feng1, Alex Bernal3, Claudia K. Derian3, Axel Ullrich4, Mathew A. Vadas1,2, and Pu Xia1,2

1 Signal Transduction Laboratory, Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science, Adelaide SA 5000, Australia
2 Department of Medicine, Adelaide University, Adelaide SA 5000, Australia
3 Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA, 19477
4 Department of Molecular Biology, Max Planck Institute for Biochemistry, 80539 Munich, Germany

Correspondence to Pu Xia: pu.xia{at}imvs.sa.gov.au

The transactivation of enhanced growth factor receptor (EGFR) by G protein–coupled receptor (GPCR) ligands is recognized as an important signaling mechanism in the regulation of complex biological processes, such as cancer development. Estrogen (E2), which is a steroid hormone that is intimately implicated in breast cancer, has also been suggested to function via EGFR transactivation. In this study, we demonstrate that E2-induced EGFR transactivation in human breast cancer cells is driven via a novel signaling system controlled by the lipid kinase sphingosine kinase-1 (SphK1). We show that E2 stimulates SphK1 activation and the release of sphingosine 1-phosphate (S1P), by which E2 is capable of activating the S1P receptor Edg-3, resulting in the EGFR transactivation in a matrix metalloprotease–dependent manner. Thus, these findings reveal a key role for SphK1 in the coupling of the signals between three membrane-spanning events induced by E2, S1P, and EGF. They also suggest a new signal transduction model across three individual ligand-receptor systems, i.e., "criss-cross" transactivation.

Abbreviations used in this paper: AO, antisense oligonucleotide; CM, conditioned media; EGFR, EGF receptor; ER, estrogen receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GPCR, G protein–coupled receptor; HB-EGF, heparin-binding EGF; mER, membrane-associated ER; MMP, matrix metalloprotease; p-EGFR, phosphorylated EGFR; p-ERK1/2, phosphorylated ERK1/2; PTX, pertussis toxin; S1P, sphingosine 1-phosphate; SphK, sphingosine kinase.


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