RET/Papillary Thyroid Carcinoma Oncogenic Signaling through the Rap1 Small GTPase.
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 Tyr(1062). 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].[1]References
- RET/Papillary Thyroid Carcinoma Oncogenic Signaling through the Rap1 Small GTPase. De Falco, V., Castellone, M.D., De Vita, G., Cirafici, A.M., Hershman, J.M., Guerrero, C., Fusco, A., Melillo, R.M., Santoro, M. Cancer Res. (2007) [Pubmed]
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