{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNUMBL is a multifunctional endocytic adaptor protein that plays a critical role in regulating cell signaling pathways in both normal development and cancer. In glioma cells, NUMBL expression is down‐regulated, and its forced expression suppresses cell migration and invasion by dampening NF‑κB activity through direct interaction with TRAF proteins—promoting K48‑linked polyubiquitination and proteasomal degradation (for example, TRAF5 and TRAF6)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In lung and other cancers, NUMBL has been implicated in modulating the metastatic process: while one study shows that deregulated (overexpressed) NUMBL can promote random tumor cell migration and invasion by suppressing a differentiation program driven by Klf4"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", another demonstrates that its downregulation lessens cell viability and invasion via inhibition of TRAF6‐induced NF‑κB activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cancer cell migration, NUMBL is a key regulator of developmental signaling and cell fate. In the nervous system, variants in NUMBL have been associated with schizophrenia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and alterations, including gene amplifications, have been observed in gliomas where NUMBL, in conjunction with related proteins, plays a role in neurogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the mammary gland, NUMBL (working with Numb) maintains myoepithelial cell identity and supports proper lactogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Its function is further modulated by regulatory microRNAs and homologous proteins: for instance, in pancreatic ductal adenocarcinoma, quercetin‐induced upregulation of let‑7c increases NUMBL expression, thereby indirectly inhibiting Notch signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", while downregulation of the closely related NumbL underscores its independent tumor suppressor role in restraining Notch activity and preventing epithelial‑to‑mesenchymal transition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, in cardiomyocytes, NUMBL collaborates with NUMB to assist in the endocytic trafficking of ERBB2, ensuring proper cell cycle withdrawal in maturing trabeculae."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional layers of NUMBL regulation have emerged from studies on angiogenesis and post‑transcriptional control. Members of the NUMB family are implicated in the regulation of VEGF receptor endocytosis during angiogenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", while in papillary thyroid cancer, the long non‑coding RNA SLC8A1‑AS1 stabilizes NUMBL mRNA via interaction with FUS, leading to decreased tumor cell proliferation, enhanced apoptosis, and reduced invasive behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Collectively, these findings reveal that NUMBL functions as a central modulator of multiple signaling cascades—including NF‑κB and Notch—that govern cell migration, survival, and differentiation in both developmental and oncogenic contexts.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Li Zhou, Qi Ma, Huili Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NUMBL interacts with TRAF6 and promotes the degradation of TRAF6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2010.01.037"}], "href": "https://doi.org/10.1016/j.bbrc.2010.01.037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20079715"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20079715"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Tao Tao, Chun Cheng, Yuhong Ji, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Analysis of coding-polymorphisms in NOTCH-related genes reveals NUMBL poly-glutamine repeat to be associated with schizophrenia in Brazilian and Danish subjects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Schizophr Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.schres.2006.06.036"}], "href": "https://doi.org/10.1016/j.schres.2006.06.036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16899352"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16899352"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Tea Blom, Annariikka Roselli, Minna Tanner, et al. 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