{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAP2B is emerging as a potent oncogenic regulator that is frequently overexpressed in a wide spectrum of human tumors. Its elevated levels have been correlated with enhanced cancer cell proliferation, migration, invasion, and a reduced apoptotic response. In lung squamous cell carcinomas, non‐small cell lung cancers, osteosarcoma, bladder cancer, renal cell carcinoma, prostate cancer, suprarenal epithelioma, cervical cancer, hepatocellular carcinoma, retinoblastoma, colorectal cancer, and even gliomas, RAP2B upregulation has been reported to support tumor growth and metastasis by activating survival pathways, inducing focal adhesion kinase phosphorylation, and upregulating matrix metalloproteinases as well as vascular endothelial growth factor. Moreover, RAP2B has been shown to counteract p53‐mediated apoptosis, thereby contributing further to oncogenic survival programs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nApart from driving tumorigenesis, RAP2B plays a critical role in signal transduction. Investigations in non‐mammalian and mammalian cell systems have shown that RAP2B is activated downstream of G(q)‐ and G(s)‐coupled receptors where cyclic AMP formation and EPAC activation lead to stimulation of phospholipase C‑ε. In human platelets, RAP2B undergoes agonist‑induced GTP binding and its localization to lipid rafts is directed by post‑translational palmitoylation—a modification essential for proper activation and subsequent platelet aggregation. Further, RAP2B has been implicated in modulating focal adhesion dynamics and matrix metalloproteinase activities, processes that are vital not only for cell migration and invasion but also for the intracellular trafficking events involved in pathogen‐containing vacuole formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its intrinsic oncogenic and signaling functions, RAP2B expression is finely tuned by multiple layers of post‑transcriptional regulation. Several microRNAs, including miR‑342‑3p, miR‑320b, miR‑194, and miR‑708, as well as long noncoding RNAs such as XIST and CCAT1 and even circular RNAs like circ_0008035, have been shown to directly target the RAP2B messenger RNA. This microRNA/lncRNA‑mediated regulation not only influences RAP2B-dependent cell survival and migration but also underscores its promise as a novel therapeutic target and biomarker for cancer treatment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yan Liu, Wenyue Sun, Kaitai Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of genes differentially expressed in human primary lung squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lung Cancer (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.lungcan.2007.01.016"}], "href": "https://doi.org/10.1016/j.lungcan.2007.01.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17316888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17316888"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xiao Xie, Hongtao Liu, Mingsong Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-342-3p targets RAP2B to suppress proliferation and invasion of non-small cell lung cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-015-3154-3"}], "href": "https://doi.org/10.1007/s13277-015-3154-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25663460"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25663460"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Gong-Yi Lv, Jun Miao, Xiao-Lin Zhang "}, {"type": "b", "children": [{"type": "t", "text": "Long Noncoding RNA XIST Promotes Osteosarcoma Progression by Targeting Ras-Related Protein RAP2B via miR-320b."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3727/096504017X14920318811721"}], "href": "https://doi.org/10.3727/096504017X14920318811721"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28409547"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28409547"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xinyue Zhang, Yunlong He, Kyoung-Hwa Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rap2b, a novel p53 target, regulates p53-mediated pro-survival function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.24364"}], "href": "https://doi.org/10.4161/cc.24364"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23535297"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23535297"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mingran Zhang, Qianfeng Zhuang, Li Cui "}, {"type": "b", "children": [{"type": "t", "text": "MiR-194 inhibits cell proliferation and invasion via repression of RAP2B in bladder cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2016.03.026"}], "href": "https://doi.org/10.1016/j.biopha.2016.03.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27133066"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27133066"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jiehui Di, Keyu Gao, Debao Qu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rap2B promotes angiogenesis via PI3K/AKT/VEGF signaling pathway in human renal cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1010428317701653"}], "href": "https://doi.org/10.1177/1010428317701653"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28691643"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28691643"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jiehui Di, Huan Cao, Juangjuan Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rap2B promotes cell proliferation, migration and invasion in prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Oncol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12032-016-0771-7"}], "href": "https://doi.org/10.1007/s12032-016-0771-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27154636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27154636"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jie-Hui Di, De-Bao Qu, Zheng Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rap2B promotes migration and invasion of human suprarenal epithelioma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-014-2174-8"}], "href": "https://doi.org/10.1007/s13277-014-2174-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24951956"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24951956"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Li Zhang, Hong-Bin Duan, Yun-Sheng Yang "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of Rap2B Inhibits the Proliferation and Invasion in Hepatocellular Carcinoma Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3727/096504016X14685034103914"}], "href": "https://doi.org/10.3727/096504016X14685034103914"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28081729"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28081729"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yi-Gen Peng, Zheng-Qun Zhang, Yan-Bin Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rap2b promotes proliferation, migration, and invasion of lung cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Recept Signal Transduct Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/10799893.2015.1122044"}], "href": "https://doi.org/10.3109/10799893.2015.1122044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26671640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26671640"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yinghua Li, Songyi Li, Lili Huang "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of Rap2B, a Ras Superfamily Protein, Inhibits Proliferation, Migration, and Invasion in Cervical Cancer Cells via Regulating the ERK1/2 Signaling Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3727/096504017X14912172235777"}], "href": "https://doi.org/10.3727/096504017X14912172235777"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28390112"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28390112"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lingling Pang, Qianqian Zhang, Yanmin Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long non-coding RNA CCAT1 promotes non-small cell lung cancer progression by regulating the miR-216a-5p/RAP2B axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Biol Med (Maywood) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1535370220961013"}], "href": "https://doi.org/10.1177/1535370220961013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33023331"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33023331"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Shuangling Zhang, Ming Zhou, Gaofeng Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and DNA methylation status of the Rap2B gene in human bronchial epithelial cells treated by cigarette smoke condensate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Inhal Toxicol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/08958378.2015.1076546"}], "href": "https://doi.org/10.3109/08958378.2015.1076546"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26308105"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26308105"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yang Fu, Kun Liu, Xi Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hsa_circ_0008035 Knockdown Inhibits Bladder Cancer Progression through miR-1184/RAP2B Axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Urol Int (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000527873"}], "href": "https://doi.org/10.1159/000527873"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36958293"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36958293"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Changming Dai, Huiming Yu, Qing Bai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-708 suppresses the proliferation, migration, and invasion of human retinoblastoma cells by targeting RAP2B, a member of the RAS oncogene family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Pol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18388/abp.2020_5872"}], "href": "https://doi.org/10.18388/abp.2020_5872"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36444911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36444911"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Jiangli Zhu, Xize Cao, Zhenshuai Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibiting S-palmitoylation arrests metastasis by relocating Rap2b from plasma membrane in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-024-07061-2"}], "href": "https://doi.org/10.1038/s41419-024-07061-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39277583"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39277583"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Sandrine Evellin, Jan Nolte, Karina Tysack, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stimulation of phospholipase C-epsilon by the M3 muscarinic acetylcholine receptor mediated by cyclic AMP and the GTPase Rap2B."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112024200"}], "href": "https://doi.org/10.1074/jbc.M112024200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11877431"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11877431"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "F Greco, F Sinigaglia, C Balduini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of the small GTPase Rap2B in agonist-stimulated human platelets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Thromb Haemost (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1538-7836.2004.01018.x"}], "href": "https://doi.org/10.1111/j.1538-7836.2004.01018.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15613030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15613030"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Ilaria Canobbio, Piera Trionfini, Gianni F Guidetti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting of the small GTPase Rap2b, but not Rap1b, to lipid rafts is promoted by palmitoylation at Cys176 and Cys177 and is required for efficient protein activation in human platelets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2008.05.016"}], "href": "https://doi.org/10.1016/j.cellsig.2008.05.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18582561"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18582561"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Jiehui Di, Hui Huang, Yan Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p53 target gene Rap2B regulates the cytoskeleton and inhibits cell spreading."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cancer Res Clin Oncol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00432-015-1948-8"}], "href": "https://doi.org/10.1007/s00432-015-1948-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25762091"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25762091"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "María Eugenia Mansilla Pareja, Maria Celeste Gaurón, Esteban Robledo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The cAMP effectors, Rap2b and EPAC, are involved in the regulation of the development of the Coxiella burnetii containing vacuole by altering the fusogenic capacity of the vacuole."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0212202"}], "href": "https://doi.org/10.1371/journal.pone.0212202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30763357"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30763357"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Faan Miao, Chenchen Cui, Dandan Zuo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rap2B promotes cell adhesion, proliferation, migration and invasion of human glioma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurooncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11060-019-03163-6"}], "href": "https://doi.org/10.1007/s11060-019-03163-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30997639"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30997639"}]}]}]}