ETS-1-mediated transcriptional up-regulation of CD44 is required for sphingosine-1-phosphate receptor subtype 3-stimulated chemotaxis.
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.
From the Department of Pathology,; the Bioactive Lipid Research Program.
Wenliang
W
Zhang
From the Department of Pathology,; the Bioactive Lipid Research Program.
Jiawei
J
Zhao
From the Department of Pathology,; the Bioactive Lipid Research Program.
Jen-Fu
JF
Lee
From the Department of Pathology,; the Bioactive Lipid Research Program.
Allison
A
Gartung
the Bioactive Lipid Research Program.
Hiba
H
Jawadi
From the Department of Pathology,; the Bioactive Lipid Research Program.
Wanyu Louis
WL
Lambiv
From the Department of Pathology,; the Bioactive Lipid Research Program,; the Karmanos Cancer Institute.
Kenneth V
KV
Honn
From the Department of Pathology,; the Bioactive Lipid Research Program,; the Karmanos Cancer Institute; the Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, Michigan 48201. Electronic address: menqjer.lee@wayne.edu.
Menq-Jer
MJ
Lee
D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis* / Q000235:genetics; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
C497483:CD44 protein, human; C494041:ETS1 protein, human; D018960:Hyaluronan Receptors; D008246:Lysophospholipids; D050784:Proto-Oncogene Protein c-ets-1; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D054460:rho-Associated Kinases; D048670:MAP Kinase Kinase 4; D013110:Sphingosine
CD44; Chemotaxis; Ets Family Transcription Factor; Jun N-terminal Kinase (JNK); Lipids; Receptors; Signal Transduction