title: Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1.
abstract: 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.
authors.affiliation: Signal Transduction Laboratory, Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science, Adelaide SA 5000, Australia.
authors.forename: Olga
authors.initials: O
authors.lastname: Sukocheva
authors.forename: Carol
authors.initials: C
authors.lastname: Wadham
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Albanese
authors.forename: Emily
authors.initials: E
authors.lastname: Verrier
authors.forename: Feng
authors.initials: F
authors.lastname: Feng
authors.forename: Alex
authors.initials: A
authors.lastname: Bernal
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Vadas
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
mesh_terms: D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008954:Models, Biological; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D000099157:Sphingosine Kinase
chemical_list: D066246:ErbB Receptors; D004967:Estrogens; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase