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J. Biol. Chem., Vol. 283, Issue 4, 2002-2009, January 25, 2008

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Evidence That Sprouty 2 Is Necessary for Sarcoma Formation by H-Ras Oncogene-transformed Human Fibroblasts^*

From the Carcinogenesis Laboratory, Department of Microbiology & Molecular Genetics and Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan 48824-1302

Sprouty 2 (Spry2) acts as an inhibitor of receptor tyrosine kinase signaling in various cellular contexts. Interestingly, Spry2 also prevents the c-Cbl-induced degradation of epidermal growth factor receptor (EGFR). We compared human fibroblasts malignantly transformed by overexpression of H-Ras^V12 oncogene to their nontransformed parental cells and found that the malignant cells express a high level of Spry2. These cells also exhibited an increase in the level of EGFR compared with their precursor cells. We found that intact EGFR was required if H-Ras-transformed cells were to grow in the absence of exogenous growth factors or form large colonies in agarose. When we decreased expression of Spry2, using a Spry2-specific shRNA, the H-Ras^V12-transformed fibroblasts could no longer form large colonies in agarose, grow in reduced levels of serum, or form tumors in athymic mice. The level of active H-Ras in these cells remained unaltered. A similar, but less pronounced, effect in tumor formation was observed when Spry2 was down-regulated in human patient-derived fibrosarcoma cell lines. In H-Ras-transformed cells Spry2 sustained the level and the downstream signaling activity of EGFR. In the parental, non-H-Ras-transformed fibroblasts, expression of Spry2 resulted in the inhibition of H-Ras and ERK activation, suggesting that the positive effect of Spry2 in tumor formation is specific to H-Ras transformation. Co-immunoprecipitation studies with H-Ras-transformed cells revealed that Spry2 and H-Ras interact and that H-Ras interacts with Spry2-binding partners, c-Cbl and CIN85, in a Spry2-dependent manner. These data show that Spry2 plays a critical role in the ability of H-Ras-transformed cells to form tumors in athymic mice.

Received for publication, November 5, 2007 , and in revised form, November 28, 2007.

^* This work was supported by the Department of Health and Human Services from the National Institutes of Health Grant CA098305 (to J. J. M.) and by a Research Assistantship (to P. L.) from Michigan State University, College of Human Medicine.

¹ To whom correspondence should be addressed: Carcinogenesis Laboratory, Food Safety and Toxicology Bldg., Michigan State University, East Lansing, MI 48824-1302. Tel.: 517-353-7785; Fax: 517-353-9004.

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