{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNicastrin (NCSTN) is a pivotal subunit of the γ‐secretase complex that mediates the intramembrane proteolysis of several type I transmembrane proteins—including the amyloid precursor protein (APP) and Notch—and has been implicated both as a candidate Alzheimer’s disease susceptibility gene and as a locus for mutations causing familial acne inversa (hidradenitis suppurativa). Its genetic association with Alzheimer’s disease and its mutation in families affected by inflammatory skin disorders underscore its broad biological relevance in human disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNCSTN undergoes extensive post‐translational processing that is essential for the proper assembly and maturation of the γ‐secretase complex. Only the mature, heavily glycosylated form of NCSTN is stably incorporated into high–molecular weight complexes with presenilin, APH‐1 and PEN‐2. Through direct interactions with these cofactors, NCSTN plays a scaffolding role that guides the complex through biosynthetic pathways—ensuring correct trafficking from the endoplasmic reticulum to the Golgi—and is itself dependent on presenilin for complete maturation. Structural studies and chimera analyses have further delineated regions within NCSTN (including its C‐terminal ectodomain and its authentic transmembrane domain) that are indispensable for interactions with other γ‐secretase components."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its architectural role within the complex, NCSTN also functions as a substrate receptor. Its extensive extracellular ectodomain appears to mediate the binding of substrates such as APP, a capacity that can be modulated by various post‐translational modifications. For example, lipid modifications like S‐palmitoylation—which influence its association with cholesterol‐rich membrane microdomains—and phosphorylation events, including those induced by stress‐activated kinases, as well as modifications by lipid peroxidation products, have been shown to affect substrate binding and, consequently, γ‐secretase activity. These findings illuminate a dynamic regulation whereby NCSTN not only promotes proper complex assembly but also fine‐tunes the proteolytic processing of key substrates."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in NCSTN function—whether through genetic mutations, aberrant post‐translational modification or misregulation of its expression—have far‐reaching implications for disease. Structural analyses and reconstitution studies in heterologous systems have provided critical insights into the architecture of NCSTN and its integration into the γ‐secretase holoenzyme, while functional studies in cellular and animal models underscore its contribution to pathological processes in Alzheimer’s disease, familial acne inversa, and even certain cancers where dysregulated Notch signaling is observed. Indeed, NCSTN overexpression has been linked to cancer stem cell properties and resistance to anti‐estrogen therapies, and targeted inhibition of its function—for instance, via monoclonal antibodies—has emerged as a promising therapeutic strategy. Thus, NCSTN is not only central to the formation of an active γ‐secretase complex but also serves as a critical modulator of substrate processing and cell signaling in diverse biological contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lars Bertram, Matthew B McQueen, Kristina Mullin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1934"}], "href": "https://doi.org/10.1038/ng1934"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17192785"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17192785"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Baoxi Wang, Wei Yang, Wen Wen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gamma-secretase gene mutations in familial acne inversa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1196284"}], "href": "https://doi.org/10.1126/science.1196284"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20929727"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20929727"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Andrew E Pink, Michael A Simpson, Nemesha Desai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "γ-Secretase mutations in hidradenitis suppurativa: new insights into disease pathogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2012.372"}], "href": "https://doi.org/10.1038/jid.2012.372"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23096707"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23096707"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Y Nomura, T Nomura, K Sakai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel splice site mutation in NCSTN underlies a Japanese family with hidradenitis suppurativa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Dermatol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2133.2012.11174.x"}], "href": "https://doi.org/10.1111/j.1365-2133.2012.11174.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22834455"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22834455"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Laura Marlow, Rosa M Canet, Sharie J Haugabook, et al. "}, {"type": "b", "children": [{"type": "t", "text": "APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(03)00797-6"}], "href": "https://doi.org/10.1016/s0006-291x(03"}, {"type": "t", "text": "00797-6) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12763021"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12763021"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Todd L Edwards, Margaret Pericak-Vance, Johnny R Gilbert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An association analysis of Alzheimer disease candidate genes detects an ancestral risk haplotype clade in ACE and putative multilocus association between ACE, A2M, and LRRTM3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet B Neuropsychiatr Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.b.30899"}], "href": "https://doi.org/10.1002/ajmg.b.30899"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19105203"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19105203"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Nobumasa Takasugi, Taisuke Tomita, Ikuo Hayashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of presenilin cofactors in the gamma-secretase complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature01506"}], "href": "https://doi.org/10.1038/nature01506"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12660785"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12660785"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Dieter Edbauer, Edith Winkler, Christian Haass, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation."}]}, {"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.132277899"}], "href": "https://doi.org/10.1073/pnas.132277899"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12048259"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12048259"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Sheu-Fen Lee, Sanjiv Shah, Hongqiao Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M208164200"}], "href": "https://doi.org/10.1074/jbc.M208164200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12297508"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12297508"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jae Yoon Leem, Shrijay Vijayan, Ping Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presenilin 1 is required for maturation and cell surface accumulation of nicastrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C200148200"}], "href": "https://doi.org/10.1074/jbc.C200148200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11943765"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11943765"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "W Taylor Kimberly, Matthew J LaVoie, Beth L Ostaszewski, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Gamma-secretase activity is associated with a conformational change of nicastrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C300095200"}], "href": "https://doi.org/10.1074/jbc.C300095200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12644462"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12644462"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Linfeng Sun, Lingyun Zhao, Guanghui Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis of human γ-secretase assembly."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1506242112"}], "href": "https://doi.org/10.1073/pnas.1506242112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25918421"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25918421"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yongjun Gu, Fusheng Chen, Nobuo Sanjo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M209499200"}], "href": "https://doi.org/10.1074/jbc.M209499200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12471034"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12471034"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Vanessa A Morais, Adam S Crystal, Donald S Pijak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M305685200"}], "href": "https://doi.org/10.1074/jbc.M305685200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12917438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12917438"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Keiro Shirotani, Dieter Edbauer, Marcus Kostka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identification of nicastrin mutants that selectively interact with APH-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2004.02447.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2004.02447.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15189355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15189355"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Anja Capell, Christoph Kaether, Dieter Edbauer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicastrin interacts with gamma-secretase complex components via the N-terminal part of its transmembrane domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C300435200"}], "href": "https://doi.org/10.1074/jbc.C300435200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14602727"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14602727"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Daniel R Dries, Sanjiv Shah, Yu-Hong Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glu-333 of nicastrin directly participates in gamma-secretase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.038737"}], "href": "https://doi.org/10.1074/jbc.M109.038737"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19729449"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19729449"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "A-Ryeong Gwon, Jong-Sung Park, Thiruma V Arumugam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1474-9726.2012.00817.x"}], "href": "https://doi.org/10.1111/j.1474-9726.2012.00817.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22404891"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22404891"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Haipeng Cheng, Kulandaivelu S Vetrivel, Renaldo C Drisdel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S-palmitoylation of gamma-secretase subunits nicastrin and APH-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M806380200"}], "href": "https://doi.org/10.1074/jbc.M806380200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19028695"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19028695"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Lan-Hsin Kuo, Ming-Kuan Hu, Wen-Ming Hsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor necrosis factor-alpha-elicited stimulation of gamma-secretase is mediated by c-Jun N-terminal kinase-dependent phosphorylation of presenilin and nicastrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e07-09-0987"}], "href": "https://doi.org/10.1091/mbc.e07-09-0987"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18667537"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18667537"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Xulun Zhang, Robert J Hoey, Guoqing Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies."}]}, {"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.1202691109"}], "href": "https://doi.org/10.1073/pnas.1202691109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22586122"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22586122"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Xiao-Chen Bai, Chuangye Yan, Guanghui Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An atomic structure of human γ-secretase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature14892"}], "href": "https://doi.org/10.1038/nature14892"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26280335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26280335"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Kulandaivelu S Vetrivel, Haipeng Cheng, William Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M407986200"}], "href": "https://doi.org/10.1074/jbc.M407986200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15322084"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15322084"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "L M Houlihan, S E Harris, M Luciano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Replication study of candidate genes for cognitive abilities: the Lothian Birth Cohort 1936."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Brain Behav (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1601-183X.2008.00470.x"}], "href": "https://doi.org/10.1111/j.1601-183X.2008.00470.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19077115"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19077115"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Anja Capell, Dirk Beher, Stefan Prokop, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gamma-secretase complex assembly within the early secretory pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M409106200"}], "href": "https://doi.org/10.1074/jbc.M409106200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15591316"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15591316"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Ylenia Lombardo, Aleksandra Filipović, Gemma Molyneux, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicastrin regulates breast cancer stem cell properties and tumor growth in vitro and in vivo."}]}, {"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.1206268109"}], "href": "https://doi.org/10.1073/pnas.1206268109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23012411"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23012411"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "X Xiao, Y He, C Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicastrin mutations in familial acne inversa impact keratinocyte proliferation and differentiation through the Notch and phosphoinositide 3-kinase/AKT signalling pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Dermatol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/bjd.14223"}], "href": "https://doi.org/10.1111/bjd.14223"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26473517"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26473517"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Leann K Massey, Alex L Mah, Mervyn J Monteiro "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20050491"}], "href": "https://doi.org/10.1042/BJ20050491"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15975090"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15975090"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Ryan R Fortna, Adam S Crystal, Vanessa A Morais, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the gamma-secretase complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M310505200"}], "href": "https://doi.org/10.1074/jbc.M310505200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14593096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14593096"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "I Hayashi, S Takatori, Y Urano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2011.265"}], "href": "https://doi.org/10.1038/onc.2011.265"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21725355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21725355"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Ylenia Lombardo, Monica Faronato, Aleksandra Filipovic, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/bcr3675"}], "href": "https://doi.org/10.1186/bcr3675"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24919951"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24919951"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "C-R Li, M-J Jiang, D-B Shen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two novel mutations of the nicastrin gene in Chinese patients with acne inversa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Dermatol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2133.2011.10372.x"}], "href": "https://doi.org/10.1111/j.1365-2133.2011.10372.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21495993"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21495993"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Tian Xie, Chuangye Yan, Rui Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of the γ-secretase component nicastrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1414837111"}], "href": "https://doi.org/10.1073/pnas.1414837111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25197054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25197054"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Jinhe Li, Gregory J Fici, Chai-An Mao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Positive and negative regulation of the gamma-secretase activity by nicastrin in a murine model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M301288200"}], "href": "https://doi.org/10.1074/jbc.M301288200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12815056"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12815056"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Yanyan He, Haoxiang Xu, Chengrang Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicastrin/miR-30a-3p/RAB31 Axis Regulates Keratinocyte Differentiation by Impairing EGFR Signaling in Familial Acne Inversa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jid.2018.07.020"}], "href": "https://doi.org/10.1016/j.jid.2018.07.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30120935"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30120935"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Chinatsu Hattori, Masashi Asai, Yoko Oma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BACE1 interacts with nicastrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0006-291X(02)00351-0"}], "href": "https://doi.org/10.1016/S0006-291X(02"}, {"type": "t", "text": "00351-0) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12054507"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12054507"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Dieter Edbauer, Christoph Kaether, Harald Steiner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Co-expression of nicastrin and presenilin rescues a loss of function mutant of APH-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M406228200"}], "href": "https://doi.org/10.1074/jbc.M406228200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15210705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15210705"}]}]}]}