{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FBXW8 is an F‐box protein that functions as the substrate recognition component of atypical SCF‐like E3 ubiquitin ligase complexes assembled with Cullin 7. These complexes mediate the polyubiquitination and subsequent proteasomal degradation of key regulatory proteins that modulate cell cycle progression, growth, and signal transduction. For example, FBXW8 directs the cytoplasmic degradation of cyclin D1 in a phosphorylation‐dependent manner, thereby ensuring proper cell cycle transition and cancer cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " FBXW8 has also been implicated in the regulation of neuronal and neurodegenerative processes by modulating the solubility and turnover of ATXN2, suggesting that its activity may alleviate toxic protein accumulations associated with polyglutamine disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Furthermore, FBXW8 is recruited by TBC1D3 upon growth factor stimulation, thereby promoting the ubiquitination and turnover of this oncoprotein, which may serve as a feedback mechanism to temper enhanced receptor signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In vivo studies underscore the developmental importance of FBXW8: mice deficient in FBXW8 display intrauterine growth retardation, abnormal placental morphology, and reduced organ size, indicating a critical role in growth regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, the FBXW8-containing Cullin 7 complex has been shown to contribute to proper insulin signaling by targeting substrates such as IRS-1 for degradation under conditions of chronic insulin exposure."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, in pancreatic cancer cells FBXW8, together with CUL7, mediates the degradation of HPK1—a kinase whose turnover is linked to proliferative signaling—thereby reinforcing the role of FBXW8 in oncogenic pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, FBXW8 levels are themselves regulated by upstream signals. For instance, miR-218 directly targets FBXW8, and modulation of this microRNA alters the expression of cell cycle regulators and the proliferation of trophoblast cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In addition, FBXW8 can form higher order complexes with other cullin-based ligases, which may enhance the efficiency of ubiquitination of additional substrates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these studies demonstrate that FBXW8 plays a pivotal role in maintaining cellular homeostasis by targeting specific proteins for degradation, thereby influencing cell cycle dynamics, growth, differentiation, and stress responses.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroshi Okabe, Sang-Hyun Lee, Janyaporn Phuchareon, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Both ubiquitin ligases FBXW8 and PARK2 are sequestrated into insolubility by ATXN2 PolyQ expansions, but only FBXW8 expression is dysregulated."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0121089"}], "href": "https://doi.org/10.1371/journal.pone.0121089"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25790475"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25790475"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Chen Kong, Dmitri Samovski, Priya Srikanth, et al. 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