Mutation Analysis of RAP1 Gene in Papillary Thyroid Carcinomas

Abstract

Abstract. In human papillary thyroid carcinomas (PTCs), the genetic alterations of RET/PTC, RAS or BRAF account for about 60-70% of cases with practically no overlap, providing strong genetic evidence that constitutive active signaling along MAPK pathway is critical for PTC development. In the remaining 30-40% of the cases, the oncogenes are still unknown. RAP1 is a member of the RAS family of small G proteins transmitting signals from the TSH-R to MAPK pathway using cAMP-dependent mechanism in thyroid cells. RAP1 was shown to have both mitogenic and tumorigenic properties in certain systems; however, the potential role of RAP1 mutation in thyroid carcinogenesis has yet to be elucidated. In this study, we analyzed the mutational status of RAP1 gene in 36 Russian patients with PTCs without RET/ PTC rearrangement, BRAF mutation or RAS mutation. No mutations in either RAP1A or RAP1B genes were found. These results suggest that RAP1 mutation does not play an important role in PTC pathogenesis.

MicroRNA-100 regulates SW620 colorectal cancer cell proliferation and invasion by targeting RAP1B

“…RAP1B localizes to cellular membranes and has been shown to regulate integrin-mediated cell signaling. It also plays a role in regulating outside-in signaling in platelets (16)(17)(18)(19)(20). Recently, Rap1B was reported to be regulated by miR-139 in colorectal cancer and regulate by miR-518b in esophageal squamous cell carcinoma (21,22).…”

Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells

“…It has been further proposed that both the inhibitory and enhancing effects of cAMP on cell proliferation are mediated by Rap1, which can act either antagonistically or synergistically with Ras, depending on the cellular context (Bos et al, 2001;Schmitt and Stork, 2001;Ribeiro-Neto et al, 2002). Thus far, no Rap1-activating mutations have been identified in human tumors (Gyan et al, 2005;Zemojtel et al, 2006;Matsuse et al, 2009). However, this does not exclude the possibility that Rap1 is a potential member in oncogenesis via alternative mechanisms, such as overexpression or downregulation of Rap1, or any of the regulatory proteins acting upstream and downstream of Rap1 (Altschuler and Ribeiro-Neto, 1998;Ishida et al, 2003;Yajnik et al, 2003;Tsygankova et al, 2007;Bailey et al, 2009).…”

Tumor Cell Migration and Invasion Are Enhanced by Depletion of Rap1 GTPase-activating Protein (Rap1GAP)

“…Stable expression of activated Rap enhanced metastasis in prostate cancer cells and the infiltration of breast cancer cells into the vasculature (25,26). However, the significance of these studies to human tumors is unclear in that activating mutations in Rap have not been reported (27). Downregulation of Rap1GAP 2 is widespread in human tumors (28 -33).…”