NOTCH3 Gene

HGNC Family	Ankyrin repeat domain containing (ANKRD)
Name	notch 3
Description	This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNOTCH3 serves as a pivotal regulator in cancer biology by promoting oncogenic processes and the maintenance of cancer stem cell properties. In diverse malignancies such as breast, lung, ovarian, and squamous cell carcinomas, NOTCH3 activation supports self‐renewal, tumor initiation, and chemoresistance. For instance, interleukin‐6–driven signaling in breast cancer stem/progenitor cells leads to NOTCH3–dependent upregulation of oncogenic effectors, while in lung and ovarian cancers, enhanced NOTCH3 activity enriches for tumor‐propagating, drug‐resistant cell populations. In addition, microRNAs (e.g. miR‐136 and miR‐613) modulate NOTCH3 expression, thereby reprogramming tumor cells and altering their proliferative and survival capacities."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the vasculature, NOTCH3 is crucial for the regulation of smooth muscle cell differentiation, proliferation, and overall vessel homeostasis. Elevated NOTCH3 expression underlies pathological states such as pulmonary arterial hypertension and is central to the pathogenesis of CADASIL—a genetic small‐vessel disease characterized by mutant NOTCH3 accumulation and aggregation. Experimental deletion or inhibition of NOTCH3 in animal models prevents vascular remodeling and disease onset, while endothelial cues drive its expression in mural cells, thereby influencing vessel maturation and function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNOTCH3 also plays an important role within the hematopoietic compartment and the tumor microenvironment, influencing cell–cell communication that governs lymphoid differentiation and leukemogenesis. Aberrant NOTCH3 signaling has been implicated in T‐cell acute lymphoblastic leukemia—where its inhibition reduces cell proliferation and survival—and contributes to the anti–apoptotic support provided by stromal cells in B–cell lineage contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in oncogenesis and vascular biology, NOTCH3 is instrumental in modulating cellular differentiation, senescence, and tissue remodeling. Post‐translational modifications, such as hydroxylation of its ankyrin repeat domain, fine–tune NOTCH3 signaling outputs, while its ability to induce the cyclin–dependent kinase inhibitor p21 links its activity to cellular senescence and tumor suppression. In addition, structural rearrangements in NOTCH3 have been observed in distinct tumor subtypes, underscoring its context–dependent dual roles in promoting differentiation versus sustaining malignancy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pasquale Sansone, Gianluca Storci, Catia Giovannini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1634/stemcells.2006-0442"}], "href": "https://doi.org/10.1634/stemcells.2006-0442"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17158237"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17158237"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jun Konishi, Keiko S Kawaguchi, Huan Vo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-07-1022"}], "href": "https://doi.org/10.1158/0008-5472.CAN-07-1022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17804716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17804716"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Pasquale Sansone, Gianluca Storci, Simona Tavolari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI32533"}], "href": "https://doi.org/10.1172/JCI32533"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18060036"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18060036"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "James P Sullivan, Monica Spinola, Michael Dodge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-10-0881"}], "href": "https://doi.org/10.1158/0008-5472.CAN-10-0881"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21118965"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21118965"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rita João Guerreiro, Ebba Lohmann, Emma Kinsella, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2011.10.009"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2011.10.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22153900"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22153900"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shannon M McAuliffe, Stefanie L Morgan, Gregory A Wyant, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1206400109"}], "href": "https://doi.org/10.1073/pnas.1206400109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23019585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23019585"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Khaled A Hassan, Luo Wang, Hasan Korkaya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-12-0370"}], "href": "https://doi.org/10.1158/1078-0432.CCR-12-0370"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23444212"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23444212"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Syed A Ali, Verline Justilien, Lee Jamieson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2016.02.012"}], "href": "https://doi.org/10.1016/j.ccell.2016.02.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26977885"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26977885"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ju-Yeon Jeong, Haeyoun Kang, Tae Hoen Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2016.11.017"}], "href": "https://doi.org/10.1016/j.canlet.2016.11.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27887917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27887917"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Huihua Cai, Jie Yao, Yong An, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA HOTAIR acts a competing endogenous RNA to control the expression of notch3 via sponging miR-613 in pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.16462"}], "href": "https://doi.org/10.18632/oncotarget.16462"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28415631"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28415631"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Mitsuteru Natsuizaka, Kelly A Whelan, Shingo Kagawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-017-01500-9"}], "href": "https://doi.org/10.1038/s41467-017-01500-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29170450"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29170450"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Chungang Liu, Limei Liu, Xuejiao Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem-like Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-17-1236"}], "href": "https://doi.org/10.1158/0008-5472.CAN-17-1236"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29259010"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29259010"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "David Morrow, Agnieszka Scheller, Yvonne A Birney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch-mediated CBF-1/RBP-J{kappa}-dependent regulation of human vascular smooth muscle cell phenotype in vitro."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00198.2005"}], "href": "https://doi.org/10.1152/ajpcell.00198.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15987768"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15987768"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Nils Peters, Christian Opherk, Tanja Bergmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Neurol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/archneur.62.7.1091"}], "href": "https://doi.org/10.1001/archneur.62.7.1091"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16009764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16009764"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Y Kim, E J Choi, C G Choi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurology (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1212/01.wnl.0000216259.99811.50"}], "href": "https://doi.org/10.1212/01.wnl.0000216259.99811.50"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16717210"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16717210"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Marie Monet, Valérie Domenga, Barbara Lemaire, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddm042"}], "href": "https://doi.org/10.1093/hmg/ddm042"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17331978"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17331978"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Tao Wang, Martin Baron, Dorothy Trump "}, {"type": "b", "children": [{"type": "t", "text": "An overview of Notch3 function in vascular smooth muscle cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prog Biophys Mol Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.pbiomolbio.2007.07.006"}], "href": "https://doi.org/10.1016/j.pbiomolbio.2007.07.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17854869"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17854869"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Shaobo Jin, Emil M Hansson, Saara Tikka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.107.167965"}], "href": "https://doi.org/10.1161/CIRCRESAHA.107.167965"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18483410"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18483410"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Hua Liu, Simone Kennard, Brenda Lilly "}, {"type": "b", "children": [{"type": "t", "text": "NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.108.184846"}], "href": "https://doi.org/10.1161/CIRCRESAHA.108.184846"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19150886"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19150886"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Marie Monet-Leprêtre, Boris Bardot, Barbara Lemaire, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awp049"}], "href": "https://doi.org/10.1093/brain/awp049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19293235"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19293235"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Xiaodong Li, Xiaoxue Zhang, Robin Leathers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch3 signaling promotes the development of pulmonary arterial hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.2021"}], "href": "https://doi.org/10.1038/nm.2021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19855400"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19855400"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Joon Tae Park, Xu Chen, Claes G Tropè, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/ajpath.2010.100316"}], "href": "https://doi.org/10.2353/ajpath.2010.100316"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20671266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20671266"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Hua Liu, Wenbo Zhang, Simone Kennard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch3 is critical for proper angiogenesis and mural cell investment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.110.218271"}], "href": "https://doi.org/10.1161/CIRCRESAHA.110.218271"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20689064"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20689064"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Marco Duering, Anna Karpinska, Stefanie Rosner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Co-aggregate formation of CADASIL-mutant NOTCH3: a single-particle analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr237"}], "href": "https://doi.org/10.1093/hmg/ddr237"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21628316"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21628316"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Helena Schmidt, Marion Zeginigg, Marco Wiltgen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awr252"}], "href": "https://doi.org/10.1093/brain/awr252"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22006983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22006983"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Pasquale Sansone, Claudio Ceccarelli, Marjan Berishaj, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms10442"}], "href": "https://doi.org/10.1038/ncomms10442"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26858125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26858125"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Liam A Hurst, Benjamin J Dunmore, Lu Long, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms14079"}], "href": "https://doi.org/10.1038/ncomms14079"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28084316"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28084316"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Diana Bellavia, Antonio F Campese, Saula Checquolo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.062050599"}], "href": "https://doi.org/10.1073/pnas.062050599"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11891328"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11891328"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Stefano Indraccolo, Sonia Minuzzo, Massimo Masiero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-08-2791"}], "href": "https://doi.org/10.1158/0008-5472.CAN-08-2791"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19208840"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19208840"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Margherita Ghisi, Alberto Corradin, Katia Basso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2010-12-326629"}], "href": "https://doi.org/10.1182/blood-2010-12-326629"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21551231"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21551231"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Armel Hervé Nwabo Kamdje, Federico Mosna, Francesco Bifari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2010-12-326694"}], "href": "https://doi.org/10.1182/blood-2010-12-326694"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21602525"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21602525"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Kevin Wei, Ilya Korsunsky, Jennifer L Marshall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch signalling drives synovial fibroblast identity and arthritis pathology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-020-2222-z"}], "href": "https://doi.org/10.1038/s41586-020-2222-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32499639"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32499639"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Mathew L Coleman, Michael A McDonough, Kirsty S Hewitson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704102200"}], "href": "https://doi.org/10.1074/jbc.M704102200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17573339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17573339"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Laura Gramantieri, Catia Giovannini, Arianna Lanzi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Liver Int (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1478-3231.2007.01544.x"}], "href": "https://doi.org/10.1111/j.1478-3231.2007.01544.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17696940"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17696940"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Shinya Ohashi, Mitsuteru Natsuizaka, Seiji Naganuma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-11-0846"}], "href": "https://doi.org/10.1158/0008-5472.CAN-11-0846"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21890822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21890822"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Hang Cui, Yahui Kong, Mei Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch3 functions as a tumor suppressor by controlling cellular senescence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-12-3902"}], "href": "https://doi.org/10.1158/0008-5472.CAN-12-3902"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23610446"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23610446"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Marie Monet-Leprêtre, Iman Haddad, Céline Baron-Menguy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awt092"}], "href": "https://doi.org/10.1093/brain/awt092"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23649698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23649698"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Bo Xu, Yuan-Wei Zhang, Xian-Hong Tong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of microRNA profile in human cumulus granulosa cells: Identification of microRNAs that regulate Notch signaling and are associated with PCOS."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2015.01.030"}], "href": "https://doi.org/10.1016/j.mce.2015.01.030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25622783"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25622783"}]}]}]}
Synonyms	CADASIL1, CADASIL, LMNS, IMF2, CASIL
Proteins	NOTC3_HUMAN
NCBI Gene ID	4854
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

NOTCH3 has 11,729 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 137 datasets.

Click the + buttons to view associations for NOTCH3 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

NOTCH3 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by NOTCH3 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of NOTCH3 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of NOTCH3 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of NOTCH3 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of NOTCH3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of NOTCH3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of NOTCH3 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of NOTCH3 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of NOTCH3 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of NOTCH3 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of NOTCH3 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of NOTCH3 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of NOTCH3 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with NOTCH3 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with NOTCH3 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with NOTCH3 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of NOTCH3 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of NOTCH3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of NOTCH3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with NOTCH3 gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with NOTCH3 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing NOTCH3 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of NOTCH3 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing NOTCH3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing NOTCH3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing NOTCH3 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing NOTCH3 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with NOTCH3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with NOTCH3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing NOTCH3 protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of NOTCH3 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with NOTCH3 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with NOTCH3 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with NOTCH3 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of NOTCH3 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by NOTCH3 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving NOTCH3 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving NOTCH3 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with NOTCH3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with NOTCH3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.