Abstract
Sphingosine-1-phosphate (S1P)-regulated chemotaxis plays critical roles in various physiological and pathophysiological conditions. S1P-regulated chemotaxis is mediated by the S1P family of G-protein-coupled receptors. However, molecular details of the S1P-regulated chemotaxis are incompletely understood. Cultured human lung adenocarcinoma cell lines abundantly express S1P receptor subtype 3 (S1P3), thus providing a tractable in vitro system to characterize molecular mechanism(s) underlying the S1P3 receptor-regulated chemotactic response. S1P treatment enhances CD44 expression and induces membrane localization of CD44 polypeptides via the S1P3/Rho kinase (ROCK) signaling pathway. Knockdown of CD44 completely diminishes the S1P-stimulated chemotaxis. Promoter analysis suggests that the CD44 promoter contains binding sites of the ETS-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) transcriptional factor. ChIP assay confirms that S1P treatment stimulates the binding of ETS-1 to the CD44 promoter region. Moreover, S1P induces the expression and nuclear translocation of ETS-1. Knockdown of S1P3 or inhibition of ROCK abrogates the S1P-induced ETS-1 expression. Furthermore, knockdown of ETS-1 inhibits the S1P-induced CD44 expression and cell migration. In addition, we showed that S1P3/ROCK signaling up-regulates ETS-1 via the activity of JNK. Collectively, we characterized a novel signaling axis, i.e., ROCK-JNK-ETS-1-CD44 pathway, which plays an essential role in the S1P3-regulated chemotactic response.
Highlights
S1P3-mediated chemotaxis plays a pivotal role in various physiological and pathophysiological activities
S1P-stimulated CD44 Expression Is Mediated by the S1P3 Receptor/ROCK Signaling Pathway—Previously, we showed that S1P3 receptors are abundantly expressed in H1793, H1792, H23, and H1650 human lung adenocarcinoma cell lines, whereas S1P3 receptors are barely detected in HBEC2-KT normal lung epithelial cells [39]
We showed that S1P3-mediated CD44 upregulation requires ROCK1 activity (Fig. 2F)
Summary
S1P3-mediated chemotaxis plays a pivotal role in various physiological and pathophysiological activities. We characterized a novel signaling axis, i.e., ROCK-JNK-ETS-1-CD44 pathway, which plays an essential role in the S1P3-regulated chemotactic response. We and others have shown that S1P1 and S1P3 receptor-mediated signaling pathways play critical roles in endothelial cell chemotaxis, adherens junction assembly, endothelial morphogenesis, and angiogenic responses [10, 15, 16]. S1P-regulated chemotactic response has been shown to play critical roles in various physiological and pathophysiological conditions, including angiogenesis [15, 16], vascular maturation [26], atherosclerosis [19], lymphocyte egress from lymphoid organs [27, 28], multiple sclerosis [29], and the invasion and metastasis of tumor cells [30, 31].
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