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RET/Papillary Thyroid Carcinoma Oncogenic Signaling through the Rap1 Small GTPase

¹ Istituto di Endocrinologia ed Oncologia Sperimentale del CNR "G.Salvatore", c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita' Federico II, Naples, Italy; ² Endocrinology and Metabolism Division, University of California at Los Angeles School of Medicine, Los Angeles, California; and ³ Instituto de Biologia Molecular y Celular del Cancer, Centro de Investigacion del Cancer (Consejo Superior de Investigaciones Científicas-Universidad de Salamanca), University of Salamanca, Salamanca, Spain

Requests for reprints: Massimo Santoro, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Medical School, University "Federico II" of Naples, via Sergio Pansini 5, 80131 Naples, Italy. Phone: 39-081-7463056; Fax: 39-081-7463037; E-mail: masantor{at}unina.it.

RET/papillary thyroid carcinoma (PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC1 activates the Rap1 small GTPase. The activation of Rap1 was dependent on the phosphorylation of RET Tyr¹⁰⁶². RET/PTC1 recruited a complex containing growth factor receptor binding protein 2–associated binding protein 1 (Gab1), CrkII (v-crk sarcoma virus CT10 oncogene homologue II), and C3G (Rap guanine nucleotide exchange factor 1). By using dominant-negative and small interfering duplex (small interfering RNA) oligonucleotides, we show that RET/PTC1–mediated Rap1 activation was dependent on CrkII, C3G, and Gab1. Activation of Rap1 was involved in the RET/PTC1–mediated stimulation of the BRAF kinase and the p42/p44 mitogen-activated protein kinases. Proliferation and stress fiber formation of RET/PTC1–expressing PC Cl 3 thyroid follicular cells were inhibited by the dominant-negative Rap1(N17) and by Rap1–specific GTPase-activating protein. Thus, Rap1 is a downstream effector of RET/PTC and may contribute to the transformed phenotype of RET/PTC–expressing thyrocytes. [Cancer Res 2007;67(1):381–90]

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