This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sutterlüty, H. Articles by Berger, W. Search for Related Content PubMed PubMed Citation Articles by Sutterlüty, H. Articles by Berger, W.

---

Signaling and Regulation

Down-Regulation of Sprouty2 in Non–Small Cell Lung Cancer Contributes to Tumor Malignancy via Extracellular Signal-Regulated Kinase Pathway-Dependent and -Independent Mechanisms

¹ Institute of Cancer Research, Department of Medicine I, Medical University Vienna and ² Institute for Pathology and Bacteriology, Otto Wagner Hospital Baumgartner Höhe, Vienna, Austria

Requests for reprints: Hedwig Sutterlüty, Institute of Cancer Research, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria. Phone: 43-1-427765244; Fax: 43-1-427765196. E-mail: hedwig.sutterluety{at}meduniwien.ac.at

Sprouty (Spry) proteins function as inhibitors of receptor tyrosine kinase signaling mainly by interfering with the Ras/Raf/mitogen-activated protein kinase cascade, a pathway known to be frequently deregulated in human non–small cell lung cancer (NSCLC). In this study, we show a consistently lowered Spry2 expression in NSCLC when compared with the corresponding normal lung epithelium. Based on these findings, we investigated the influence of Spry2 expression on the malignant phenotype of NSCLC cells. Ectopic expression of Spry2 antagonized mitogen-activated protein kinase activity and inhibited cell migration in cell lines homozygous for K-Ras wild type, whereas in NSCLC cells expressing mutated K-Ras, Spry2 failed to diminish extracellular signal-regulated kinase (ERK) phosphorylation. Nonetheless, Spry2 significantly reduced cell proliferation in all investigated cell lines and blocked tumor formation in mice. Accordingly, a Spry2 mutant unable to inhibit ERK phosphorylation reduced cell proliferation significantly but less pronounced compared with the wild-type protein. Therefore, we conclude that Spry2 interferes with ERK phosphorylation and another yet unidentified pathway. Our results suggest that Spry2 plays a role as tumor suppressor in NSCLC by antagonizing receptor tyrosine kinase–induced signaling at different levels, indicating feasibility for the usage of Spry in targeted gene therapy of NSCLC. (Mol Cancer Res 2007;5(5):509–20)

This article has been cited by other articles:

				D. Sayed, S. Rane, J. Lypowy, M. He, I.-Y. Chen, H. Vashistha, L. Yan, A. Malhotra, D. Vatner, and M. Abdellatif MicroRNA-21 Targets Sprouty2 and Promotes Cellular Outgrowths Mol. Biol. Cell, August 1, 2008; 19(8): 3272 - 3282. [Abstract] [Full Text] [PDF]

				P. Lito, B. D. Mets, S. Kleff, S. O'Reilly, V. M. Maher, and J. J. McCormick Evidence That Sprouty 2 Is Necessary for Sarcoma Formation by H-Ras Oncogene-transformed Human Fibroblasts J. Biol. Chem., January 25, 2008; 283(4): 2002 - 2009. [Abstract] [Full Text] [PDF]