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

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 1; pp. 381 - 390
• Main Authors: DE FALCO, Valentina, CASTELLONE, Maria Domenica, DE VITA, Gabriella, CIRAFICI, Anna Maria, HERSHMAN, Jerome M, GUERRERO, Carmen, FUSCO, Alfredo, MELILLO, Rosa Marina, SANTORO, Massimo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 2007
• Subjects: Actins - metabolism; Adaptor Proteins, Signal Transducing - metabolism; Antineoplastic agents; Biological and medical sciences; Carcinoma, Papillary - enzymology; Carcinoma, Papillary - genetics; Carcinoma, Papillary - pathology; Cell Growth Processes - physiology; Cell Line, Tumor; Humans; Medical sciences; Monomeric GTP-Binding Proteins - genetics; Monomeric GTP-Binding Proteins - metabolism; Pharmacology. Drug treatments; Proto-Oncogene Proteins B-raf - biosynthesis; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins c-crk - metabolism; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - metabolism; rap1 GTP-Binding Proteins - genetics; rap1 GTP-Binding Proteins - metabolism; Signal Transduction; Thyroid Neoplasms - enzymology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Transfection; Tumors; Rap1 protein; Signal transduction; Enzyme; Triphosphoric monoester hydrolases; C-Onc gene; dGTPase; Hydrolases; Esterases; Carcinogenesis; Protooncogene; Papillary thyroid carcinoma; G protein
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-06-0981

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.