Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1.
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.
Sukocheva
Olga
O
Signal Transduction Laboratory, Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science, Adelaide SA 5000, Australia.
Wadham
Carol
C
Holmes
Andrew
A
Albanese
Nathaniel
N
Verrier
Emily
E
Feng
Feng
F
Bernal
Alex
A
Derian
Claudia K
CK
Ullrich
Axel
A
Vadas
Mathew A
MA
Xia
Pu
P
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
D066246:ErbB Receptors; D004967:Estrogens; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase