{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTBC1D3 is a hominoid‐specific gene that plays a critical role in neural development. Its expression in cortical progenitors induces the delamination of ventricular radial glia and promotes the formation of self‐renewing basal progenitors—known as outer radial glia—that are abundantly found in primates. This activity not only contributes to enhanced progenitor proliferation but also appears to underlie cortical expansion and folding, processes that are essential for higher brain function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its developmental role, TBC1D3 modulates multiple growth factor receptor signaling pathways that contribute to oncogenesis. By enhancing epidermal growth factor (EGF)– and insulin/IGF-1–mediated signaling, TBC1D3 delays receptor degradation—partly by suppressing receptor ubiquitination—and consequently prolongs downstream Ras, Akt, and ERK activation. These actions increase cell proliferation and survival in both human and mouse models, while its interaction with microtubule components further stabilizes receptor signaling complexes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTBC1D3 also contributes to cancer cell migration. It upregulates expression of factors such as oxidized low density lipoprotein receptor 1 (OLR1) in a mechanism that involves activation of TNFα/NF-κB signaling, thereby promoting the motility of breast cancer cells. Moreover, interactions with calmodulin (CaM) protect TBC1D3 from growth factor–induced ubiquitination and degradation, further enhancing its capacity to sustain oncogenic signaling and migratory behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe precise cellular levels and activity of TBC1D3 are controlled by complex post-translational modifications. Growth factor stimulation triggers TBC1D3 ubiquitination and degradation via the CUL7 E3 ligase complex—a process that is modulated by its phosphorylation status as well as its palmitoylation. Mutations that disrupt these modifications promote mislocalization and increase degradation efficiency, underscoring the importance of tight regulation of TBC1D3 turnover in both neural development and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xiang-Chun Ju, Qiong-Qiong Hou, Ai-Li Sheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The hominoid-specific gene TBC1D3 promotes generation of basal neural progenitors and induces cortical folding in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.18197"}], "href": "https://doi.org/10.7554/eLife.18197"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27504805"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27504805"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Qiong-Qiong Hou, Qi Xiao, Xin-Yao Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TBC1D3 promotes neural progenitor proliferation by suppressing the histone methyltransferase G9a."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Adv (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/sciadv.aba8053"}], "href": "https://doi.org/10.1126/sciadv.aba8053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33523893"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33523893"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marisa J Wainszelbaum, Audra J Charron, Chen Kong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The hominoid-specific oncogene TBC1D3 activates Ras and modulates epidermal growth factor receptor signaling and trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M800234200"}], "href": "https://doi.org/10.1074/jbc.M800234200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18319245"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18319245"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Didier Hodzic, Chen Kong, Marisa J Wainszelbaum, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TBC1D3, a hominoid oncoprotein, is encoded by a cluster of paralogues located on chromosome 17q12."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ygeno.2006.05.009"}], "href": "https://doi.org/10.1016/j.ygeno.2006.05.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16863688"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16863688"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Marisa J Wainszelbaum, Jialu Liu, Chen Kong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TBC1D3, a hominoid-specific gene, delays IRS-1 degradation and promotes insulin signaling by modulating p70 S6 kinase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0031225"}], "href": "https://doi.org/10.1371/journal.pone.0031225"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22348058"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22348058"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ze He, Tian Tian, Dan Guo, et al. 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