{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWDFY2 is a highly conserved protein characterized by WD40 motifs and a FYVE domain that targets it to endosomal membranes. In studies using Caenorhabditis elegans and mammalian cells, WDFY2 was found to localize to a unique subset of small endosomes, where it plays an essential role in mediating transferrin uptake; its depletion by RNA interference results in strong inhibition of endocytosis, underscoring its pivotal role in early endocytic processing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn oncogenesis, aberrations in WDFY2 function are implicated in several cancers. A cancer-specific, inter-chromosomal fusion gene involving CDKN2D and WDFY2 was identified in high-grade serous ovarian carcinoma, resulting in the loss of wild-type CDKN2D and WDFY2 protein expression and the gain of a truncated WDFY2 isoform that appears to deregulate the PI3K/AKT pathway, a critical driver of cellular transformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, WDFY2 functions as a key regulator of endosomal recycling. It controls the recycling of the membrane type-1 matrix metalloproteinase (MT1‐MMP) through its localization to phosphatidylinositol 3-phosphate–enriched endosomal tubules and by interacting with the v-SNARE VAMP3. Loss of WDFY2 disrupts VAMP3 distribution, leading to increased secretion of MT1-MMP, enhanced extracellular matrix degradation, and consequently increased cell invasion—a finding that points to a tumor suppressor role for WDFY2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther evidence of its tumor suppressor function comes from studies in prostate cancer, where WDFY2 expression is significantly downregulated in tumors compared with normal tissues. Overexpression of WDFY2 in prostate cancer cell lines led to reduced cell migration and colony formation by suppressing the Akt pathway, reinforcing its potential as both a prognostic biomarker and a therapeutic target in cancer progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, WDFY2 expression is subject to transcriptional regulation by p63. Overexpression of various p63 isoforms in TP53-null cells upregulates WDFY2 expression via conserved response elements. These findings, in combination with the frequent deletion of WDFY2 in different tumor types, further support its involvement in cancer regulation and even suggest a role in developmental processes such as limb formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in endocytosis and tumor suppression, dysregulation of WDFY2 can also impact reproductive health. In patients with polycystic ovary syndrome (PCOS), elevated expression of the circular RNA circ_0115118 in endometrial stromal cells was shown to inhibit cellular mobilization and embryo implantation by sponging miR-138-1-3p, which leads to increased WDFY2 expression. This finding implicates abnormal WDFY2 activity in endometrial dysfunction and suggests it may serve as a potential therapeutic target to improve pregnancy outcomes in PCOS."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Akira Hayakawa, Deborah Leonard, Stephanie Murphy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The WD40 and FYVE domain containing protein 2 defines a class of early endosomes necessary for endocytosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0508832103"}], "href": "https://doi.org/10.1073/pnas.0508832103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16873553"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16873553"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kalpana Kannan, Cristian Coarfa, Kimal Rajapakshe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CDKN2D-WDFY2 is a cancer-specific fusion gene recurrent in high-grade serous ovarian carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1004216"}], "href": "https://doi.org/10.1371/journal.pgen.1004216"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24675677"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24675677"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marte Sneeggen, Nina Marie Pedersen, Coen Campsteijn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WDFY2 restrains matrix metalloproteinase secretion and cell invasion by controlling VAMP3-dependent recycling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-019-10794-w"}], "href": "https://doi.org/10.1038/s41467-019-10794-w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31253801"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31253801"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jianqing Wang, Xu Chen, Shijun Tong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of WDFY2 inhibits prostate cancer cell growth and migration via inactivation of Akt pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1010428317704821"}], "href": "https://doi.org/10.1177/1010428317704821"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28653900"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28653900"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Paola Monti, Yari Ciribilli, Giorgia Foggetti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "P63 modulates the expression of the WDFY2 gene which is implicated in cancer regulation and limb development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biosci Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BSR20192114"}], "href": "https://doi.org/10.1042/BSR20192114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31789342"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31789342"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Zi Yang, Fenting Liu, Jiali Bai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circ_0115118 regulates endometrial functions through the miR-138-1-3p/WDFY2 axis in patients with PCOS†."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Reprod (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/biolre/ioad017"}], "href": "https://doi.org/10.1093/biolre/ioad017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36780172"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36780172"}]}]}]}