RET/papillary thyroid carcinoma oncogenic signaling through the Rap1 small GTPase

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).B y 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.