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Molecular and Cellular Biology, June 2008, p. 4142-4151, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.01465-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Sphingosine Kinases and Sphingosine-1-Phosphate Are Critical for Transforming Growth Factor β-Induced Extracellular Signal-Regulated Kinase 1 and 2 Activation and Promotion of Migration and Invasion of Esophageal Cancer Cells{triangledown}

Anna V. Miller,1 Sergio E. Alvarez,2 Sarah Spiegel,2 and Deborah A. Lebman1*

Departments of Microbiology and Immunology,1 Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia2

Received 14 August 2007/ Returned for modification 19 October 2007/ Accepted 8 April 2008

Transforming growth factor β (TGFβ) plays a dual role in oncogenesis, acting as both a tumor suppressor and a tumor promoter. These disparate processes of suppression and promotion are mediated primarily by Smad and non-Smad signaling, respectively. A central issue in understanding the role of TGFβ in the progression of epithelial cancers is the elucidation of the mechanisms underlying activation of non-Smad signaling cascades. Because the potent lipid mediator sphingosine-1-phosphate (S1P) has been shown to transactivate the TGFβ receptor and activate Smad3, we examined its role in TGFβ activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and promotion of migration and invasion of esophageal cancer cells. Both S1P and TGFβ activate ERK1/2, but only TGFβ activates Smad3. Both ligands promoted ERK1/2-dependent migration and invasion. Furthermore, TGFβ rapidly increased S1P, which was required for TGFβ-induced ERK1/2 activation, as well as migration and invasion, since downregulation of sphingosine kinases, the enzymes that produce S1P, inhibited these responses. Finally, our data demonstrate that TGFβ activation of ERK1/2, as well as induction of migration and invasion, is mediated at least in part by ligation of the S1P receptor, S1PR2. Thus, these studies provide the first evidence that TGFβ activation of sphingosine kinases and formation of S1P contribute to non-Smad signaling and could be important for progression of esophageal cancer.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, P.O. Box 980678, Richmond, VA 23298-0678. Phone: (804) 827-0378. Fax: (804) 827-0810. E-mail: dlebman{at}vcu.edu

{triangledown} Published ahead of print on 21 April 2008.

Molecular and Cellular Biology, June 2008, p. 4142-4151, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.01465-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gellings Lowe, N., Swaney, J. S., Moreno, K. M., Sabbadini, R. A. (2009). Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-{beta}-stimulated collagen production by cardiac fibroblasts. Cardiovasc Res 82: 303-312 [Abstract] [Full Text]  


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