{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRhoBTB3 is an atypical Rho GTPase that plays a central role in membrane trafficking by directly binding to Rab9 GTPase. This interaction relieves the autoinhibition of RhoBTB3 and allows it to catalyze ATP hydrolysis, a critical step in facilitating the transport of proteins from endosomes to the trans Golgi network. In addition, RhoBTB3 localizes to carriers at the Golgi–endoplasmic reticulum interface and influences trafficking speeds as well as Golgi morphology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its function in vesicular transport, RhoBTB3 interacts with plasma membrane receptors. Notably, it binds to the 5-HT7 receptor—via both the receptor’s C-terminal tail and its third intracellular loop—when they colocalize at the plasma membrane and endoplasmic reticulum. This interaction serves to inhibit proteasomal degradation of the receptor, thereby stabilizing its presence and ensuring proper receptor signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRhoBTB3 also contributes to cell cycle regulation. On Golgi membranes, it forms part of a Cullin3 (CUL3)-dependent E3 ubiquitin ligase complex that directly binds cyclin E, catalyzing its ubiquitination. This targeting of cyclin E for proteasomal degradation is essential for a proper progression from S phase to G2, whereas loss of RhoBTB3 results in cyclin E accumulation, cell cycle arrest, and noticeable Golgi fragmentation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in trafficking and cell cycle control, RhoBTB3 acts as a scaffold that promotes the turnover of hypoxia-inducible factor α (HIFα). By directly interacting with the hydroxylase PHD2 and the von Hippel-Lindau (VHL) protein—and through dimerization with LIMD1—RhoBTB3 organizes a multi-subunit complex that facilitates the hydroxylation, ubiquitination, and subsequent degradation of HIFα. Under hypoxic conditions, this complex is compromised, leading to HIFα stabilization and contributing to metabolic reprogramming associated with cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in RhoBTB3 expression have been implicated in tumorigenesis. In breast cancer, for instance, elevated levels of RhoBTB3 correlate with increased expression of Col1a1, and its modulation affects the proliferative and invasive properties of cancer cells, pointing to a pro-tumorigenic role in this context."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, circular RNA species derived from the RHOBTB3 locus (circRHOBTB3) have emerged as important regulatory molecules in cancer. In ovarian cancer, circRHOBTB3 has been identified as a significant regulator, while in cervical cancer it has been shown to enhance proliferation, migration, invasion, and the metabolic Warburg effect by interacting with the RNA-binding protein IGF2BP3—a process that is further influenced by transcriptional regulation via NR1H4."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eric J Espinosa, Monica Calero, Khambhampaty Sridevi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2009.03.043"}], "href": "https://doi.org/10.1016/j.cell.2009.03.043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19490898"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19490898"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Maeve Long, Tilen Kranjc, Margaritha M Mysior, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA Interference Screening Identifies Novel Roles for RhoBTB1 and RhoBTB3 in Membrane Trafficking Events in Mammalian Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells9051089"}], "href": "https://doi.org/10.3390/cells9051089"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32354068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32354068"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Anne Matthys, Kathleen Van Craenenbroeck, Béatrice Lintermans, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RhoBTB3 interacts with the 5-HT7a receptor and inhibits its proteasomal degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2011.12.027"}], "href": "https://doi.org/10.1016/j.cellsig.2011.12.027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22245496"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22245496"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Albert Lu, Suzanne R Pfeffer "}, {"type": "b", "children": [{"type": "t", "text": "Golgi-associated RhoBTB3 targets cyclin E for ubiquitylation and promotes cell cycle progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.201305158"}], "href": "https://doi.org/10.1083/jcb.201305158"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24145166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24145166"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Chen-Song Zhang, Qi Liu, Mengqi Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cr.2015.90"}], "href": "https://doi.org/10.1038/cr.2015.90"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26215701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26215701"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kyungho Kim, Youn-Jae Kim "}, {"type": "b", "children": [{"type": "t", "text": "RhoBTB3 Regulates Proliferation and Invasion of Breast Cancer Cells via Col1a1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cells (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.14348/molcells.2022.2037"}], "href": "https://doi.org/10.14348/molcells.2022.2037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35698915"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35698915"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yalan Sun, Yanfang Liu, He Chen, et al. 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