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.

Sphingolipid in Lung Cancer Pathogenesis and Therapy

“…SphK1, a major enzyme that generates S1P, was found to be overexpressed in lung patient samples [43]. The SphK/S1P pathway was shown to mediate the E2-induced transactivation of EGFR, which is associated with carcinogenesis in lung cancer cells [44]. It has also been reported that expression of the oncogenic K-Ras leads to plasma membrane localization of SphK1 and increased S1P level [45].…”

Breast Cancer, Estrogen Receptor and Ligands

“…Since most of GPR30-expressing tissues are considered to be ER positive, it seems likely to assume that their estrogenic responses are partially mediated by GPR30. GPR30 demonstrably regulates the phosphorylation state of ERK1/2 [86,87,88], induces mobilisation of intracellular calcium [89,90], cAMP (cyclic adenosine monophosphate) release [87], and synthesis of phosphoinositide 3-kinase (PI3K) [90]. In the course of mER signalling, a trans-activation of epithelial growth factor receptor (EGFR), IGF-1 receptor, and human epithelial growth factor receptor type 2/neu (Her-2/neu) occurs, leading to the activation of their downstream mediators ERK1/2 and PI3K/Akt [87].…”

Involvement of Sphingosine Kinases/Sphingosine-1-Phosphate (S1P)/S1P Receptors in Breast Cancer Subtypes

“…Activated S1P 3 , in turn, enhances downstream signaling including EGFR transactivation and ERK phosphorylation [57,60]. A recent study demonstrated that both Estradiol and S1P induce rapid internalization of membrane EGFR while sustaining cytosolic/ endosome EGFR levels, indicating a delay in degradation of the EGFR [43].…”

“…The most predominantly expressed S1PR in MCF-7 cells is S1P 3 and it is capable of being activated by both Estradiol and S1P [57,[60][61][62][63]. Activated S1P 3 , in turn, enhances downstream signaling including EGFR transactivation and ERK phosphorylation [57,60].…”

“…Sphingolipid signaling in MCF-7 cells have been extensively studied to fill the black box between hormone stimulus (often estradiol) and its effect on tumorigenes due high ER expressions in these cells. Estradiol, a steroid hormone widely used to stimulate ER, activates SphK1 and increases both intracellular and extracellular S1P [60]. Released S1P is capable of binding to S1PRs as discussed earlier and activate downstream signaling in an autocrine and/or paracrine manner [11].…”