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J. Biol. Chem., Vol. 282, Issue 9, 6415-6424, March 2, 2007

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Ras/ERK1/2-mediated STAT3 Ser⁷²⁷ Phosphorylation by Familial Medullary Thyroid Carcinoma-associated RET Mutants Induces Full Activation of STAT3 and Is Required for c-fos Promoter Activation, Cell Mitogenicity, and Transformation^*

Iván Plaza-Menacho¹, Tineke van der Sluis^¶, Harry Hollema^¶, Oliver Gimm^||, Charles H. C. M. Buys, Anthony I. Magee^**, Clare M. Isacke, Robert M. W. Hofstra, and Bart J. L. Eggen

From the Departments of Genetics, Hanzeplein 1, 9700 RB, Groningen, ^¶Pathology, Hanzeplein 1, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands, ^||Surgery, Martin Luther University, Ernst Grube Strasse 40, 06097 Halle-Wittenberg, Germany, ^**Section of Molecular and Cellular Medicine, Imperial College, London SW7 2AZ, United Kingdom, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, United Kingdom, Developmental Genetics, Groningen Biomolecular Science and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands

The precise role of STAT3 Ser⁷²⁷ phosphorylation in RET-mediated cell transformation and oncogenesis is not well understood. In this study, we have shown that familial medullary thyroid carcinoma (FMTC) mutants RET^Y791F and RET^S891A induced, in addition to Tyr⁷⁰⁵ phosphorylation, constitutive STAT3 Ser⁷²⁷ phosphorylation. Using inhibitors and dominant negative constructs, we have demonstrated that RET^Y791F and RET^S891A induce STAT3 Ser⁷²⁷ phosphorylation via a canonical Ras/ERK1/2 pathway and that integration of the Ras/ERK1/2/ELK-1 and STAT3 pathways was required for up-regulation of the c-fos promoter by FMTC-RET. Moreover, inhibition of ERK1/2 had a more severe effect on cell proliferation and cell phenotype in HEK293 cells expressing RET^S891A compared with control and RET^WT-transfected cells. The transforming activity of RET^Y791F and RET^S891A in NIH-3T3 cells was also inhibited by U0126, indicating a role of the ERK1/2 pathway in RET-mediated transformation. To investigate the biological significance of Ras/ERK1/2-induced STAT3 Ser⁷²⁷ phosphorylation for cell proliferation and transformation, N-Ras-transformed NIH-3T3 cells were employed. These cells displayed elevated levels of activated ERK1/2 and Ser⁷²⁷-phosphorylated STAT3, which were inhibited by treatment with U0126. Importantly, overexpression of STAT3, in which the Ser⁷²⁷ was mutated into Ala (STAT3^S727A), rescued the transformed phenotype of N-Ras-transformed cells. Immunohistochemistry in tumor samples from FMTC patients showed strong nuclear staining of phosphorylated ERK1/2 and Ser⁷²⁷ STAT3. These data show that FMTC-RET mutants activate a Ras/ERK1/2/STAT3 Ser⁷²⁷ pathway, which plays an important role in cell mitogenicity and transformation.

Received for publication, September 20, 2006 , and in revised form, January 5, 2007.

^* This work was supported by grants from the Ubbo Emmius Foundation University of Groningen, Graduate School for Drug Exploration, Medical Research Council, and Breakthrough Breast Cancer Research Centre. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Molecular Cell Biology, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Rd., SW3 6JB London, UK. Tel.: 44-207-153-5168; Fax: 44-207-153-5340; E-mail: ivan.plaza-menacho{at}icr.ac.uk.

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