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J. Biol. Chem., Vol. 283, Issue 29, 20330-20341, July 18, 2008

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G₁₃-dependent Activation of MAPK by Thyrotropin^*

Thomas R. H. Büch, Heike Biebermann, Hermann Kalwa, Olaf Pinkenburg, Denise Hager, Holger Barth^¶, Klaus Aktories^||, Andreas Breit, and Thomas Gudermann¹

From the Institut für Pharmakologie und Toxikologie, Philipps-Universität, Karl-von-Frisch-Strasse 1, 35033 Marburg, Germany, Klinik und Poliklinik für Kinderheilkunde, Virchow-Klinikum der Humboldt-Universität, 13353 Berlin, Germany, ^¶Institut für Pharmakologie und Toxikologie, Universitätsklinikum Ulm, 89081 Ulm, Germany, and ^||Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, 79104 Freiburg, Germany

Stimulation of the thyrotropin receptor (TSHR) activates G proteins of all four subfamilies (G_s, G_i/o, G_q/11, and G_12/13). Whereas G_s/cAMP-dependent cellular responses upon TSHR stimulation are well established, other signaling pathways are less characterized. We evaluated TSH-elicited cellular responses in human follicular thyroid carcinoma cells stably expressing the TSHR and in primary, nonneoplastic human thyrocytes. In these cellular models, stimulation with TSH caused activation of p44/42 MAPK and subsequent induction of c-Fos. MAPK stimulation occurred independently of G_s, G_i/o, and G_q/11 signaling. Dominant negative constructs of G₁₂ or G₁₃ as well as shRNA-mediated suppression of G₁₂ or G₁₃ revealed that MAPK activation was dependent on G₁₃ but not on G₁₂ signaling. Furthermore, G₁₃-dependent transactivation of the epidermal growth factor receptor was necessary for MAPK activation in follicular carcinoma cells, whereas EGFR was not involved in MAPK activation in nonneoplastic primary thyrocytes. The use of bacterial inhibitors of monomeric GTPases revealed that MAPK activation proceeded independently of Rho proteins but was clostridial toxin B-sensitive, suggesting involvement of Cdc42 or Rac. Thus, our data shed new light on cAMP-independent TSHR signaling and identify the first G₁₃-dependent TSHR signaling pathway in human thyrocytes.

Received for publication, January 9, 2008 , and in revised form, April 22, 2008.

^* This work was supported by the Deutsche Forschungsgemeinschaft Grant TR17, project C4. 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. Tel.: 49-6421-2865000; Fax: 49-6421-2865600; E-mail: guderman{at}staff.uni-marburg.de.

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