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    NCSTN nicastrin [ Homo sapiens (human) ]

    Gene ID: 23385, updated on 27-Aug-2016
    Official Symbol
    NCSTNprovided by HGNC
    Official Full Name
    nicastrinprovided by HGNC
    Primary source
    HGNC:HGNC:17091
    See related
    Ensembl:ENSG00000162736 HPRD:05584; MIM:605254; Vega:OTTHUMG00000033110
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    ATAG1874
    Summary
    This gene encodes a type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. The encoded protein cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for gamma-secretase complex assembly. The cleavage of beta-amyloid precursor protein yields amyloid beta peptide, the main component of the neuritic plaque and the hallmark lesion in the brains of patients with Alzheimer's disease; however, the nature of the encoded protein's role in Alzheimer's disease is not known for certain. Mutations in this gene are associated with familial acne inversa. A pseudogene of this gene is present on chromosome 21. Alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Feb 2014]
    Orthologs
    Location:
    1q22-q23
    Exon count:
    19
    Annotation release Status Assembly Chr Location
    108 current GRCh38.p7 (GCF_000001405.33) 1 NC_000001.11 (160343056..160358952)
    105 previous assembly GRCh37.p13 (GCF_000001405.25) 1 NC_000001.10 (160313063..160328742)

    Chromosome 1 - NC_000001.11Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC107985219 Neighboring gene peroxisomal biogenesis factor 19 Neighboring gene coatomer protein complex subunit alpha Neighboring gene SUMO1 pseudogene 3 Neighboring gene uncharacterized LOC105371466 Neighboring gene nescient helix-loop-helix 1 Neighboring gene RNA, U4 small nuclear 42, pseudogene

    GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

    • Activated NOTCH1 Transmits Signal to the Nucleus, organism-specific biosystem (from REACTOME)
      Activated NOTCH1 Transmits Signal to the Nucleus, organism-specific biosystemMature NOTCH1 heterodimer on the cell surface is activated by one of its ligands: DLL1 (Cordle et al. 2008, Jarriault et al. 1998), DLL4 (Benedito et al. 2009), JAG1 (Li et al. 1998, Benedito et al. ...
    • Alzheimer's disease, organism-specific biosystem (from KEGG)
      Alzheimer's disease, organism-specific biosystemAlzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-b...
    • Alzheimer's disease, conserved biosystem (from KEGG)
      Alzheimer's disease, conserved biosystemAlzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-b...
    • Alzheimers Disease, organism-specific biosystem (from WikiPathways)
      Alzheimers Disease, organism-specific biosystemThis pathway displays current genes, proteolytic events and other processes associated with the progression of Alzheimer's disease. This pathway was adapted from KEGG on 10/7/2011. Note: mitochondria...
    • Axon guidance, organism-specific biosystem (from REACTOME)
      Axon guidance, organism-specific biosystemAxon guidance / axon pathfinding is the process by which neurons send out axons to reach the correct targets. Growing axons have a highly motile structure at the growing tip called the growth cone, w...
    • Cell death signalling via NRAGE, NRIF and NADE, organism-specific biosystem (from REACTOME)
      Cell death signalling via NRAGE, NRIF and NADE, organism-specific biosystemp75NTR is a key regulator of neuronal apoptosis, both during development and after injury. Apoptosis is triggered by binding of either mature neurotrophin or proneurotrophin (proNGF, proBDNF). ProNG...
    • Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants, organism-specific biosystem (from REACTOME)
      Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants, organism-specific biosystemWhen found in cis, HD and PEST domain mutations act synergistically, increasing NOTCH1 transcriptional activity up to ~40-fold, compared with up to ~10-fold and up to ~2-fold increase with HD mutatio...
    • Constitutive Signaling by NOTCH1 PEST Domain Mutants, organism-specific biosystem (from REACTOME)
      Constitutive Signaling by NOTCH1 PEST Domain Mutants, organism-specific biosystemAs NOTCH1 PEST domain is intracellular, NOTCH1 PEST domain mutants are expected to behave as the wild-type NOTCH1 with respect to ligand binding and proteolytic cleavage mediated activation of signal...
    • Degradation of the extracellular matrix, organism-specific biosystem (from REACTOME)
      Degradation of the extracellular matrix, organism-specific biosystemMatrix metalloproteinases (MMPs), previously referred to as matrixins because of their role in degradation of the extracellular matrix (ECM), are zinc and calcium dependent proteases belonging to the...
    • Delta-Notch Signaling Pathway, organism-specific biosystem (from WikiPathways)
      Delta-Notch Signaling Pathway, organism-specific biosystemThere are 4 Notch receptors in humans (Notch 1-4) that bind to a family of 5 ligands (Jagged 1 and 2 and Delta-like 1-3). The Notch receptors are expressed on the cell surface as heterodimeric protei...
    • Developmental Biology, organism-specific biosystem (from REACTOME)
      Developmental Biology, organism-specific biosystemAs a first step towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of three kinds of processes have been annotated. These are a...
    • Disease, organism-specific biosystem (from REACTOME)
      Disease, organism-specific biosystemBiological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular ...
    • Diseases of signal transduction, organism-specific biosystem (from REACTOME)
      Diseases of signal transduction, organism-specific biosystemSignaling processes are central to human physiology (e.g., Pires-da Silva & Sommer 2003), and their disruption by either germ-line and somatic mutation can lead to serious disease. Here, the molecula...
    • EPH-Ephrin signaling, organism-specific biosystem (from REACTOME)
      EPH-Ephrin signaling, organism-specific biosystemDuring the development process cell migration and adhesion are the main forces involved in morphing the cells into critical anatomical structures. The ability of a cell to migrate to its correct dest...
    • EPH-ephrin mediated repulsion of cells, organism-specific biosystem (from REACTOME)
      EPH-ephrin mediated repulsion of cells, organism-specific biosystemDespite high-affinity multimeric interaction between EPHs and ephrins (EFNs), the cellular response to EPH-EFN engagement is usually repulsion between the two cells and signal termination. These repu...
    • Extracellular matrix organization, organism-specific biosystem (from REACTOME)
      Extracellular matrix organization, organism-specific biosystemThe extracellular matrix is a component of all mammalian tissues, a network consisting largely of the fibrous proteins collagen, elastin and associated-microfibrils, fibronectin and laminins embedded...
    • NOTCH2 Activation and Transmission of Signal to the Nucleus, organism-specific biosystem (from REACTOME)
      NOTCH2 Activation and Transmission of Signal to the Nucleus, organism-specific biosystemSimilar to NOTCH1, NOTCH2 is activated by Delta-like and Jagged ligands (DLL/JAG) expressed in trans on a neighboring cell (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004...
    • NRIF signals cell death from the nucleus, organism-specific biosystem (from REACTOME)
      NRIF signals cell death from the nucleus, organism-specific biosystemNRIF (nuclear receptor-interacting factor) is a DNA binding protein that is essential for p75-mediated apoptosis in retina and sympathetic neurons. Neurotrophin or proneurotrophin binding to p75TR in...
    • Notch Signaling Pathway, organism-specific biosystem (from WikiPathways)
      Notch Signaling Pathway, organism-specific biosystemThe Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch pro...
    • Notch signaling, organism-specific biosystem (from KEGG)
      Notch signaling, organism-specific biosystemFunctional set; Cellular processes; Cell signaling
    • Notch signaling, conserved biosystem (from KEGG)
      Notch signaling, conserved biosystemFunctional set; Cellular processes; Cell signaling
    • Notch signaling pathway, organism-specific biosystem (from KEGG)
      Notch signaling pathway, organism-specific biosystemThe Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch pro...
    • Notch signaling pathway, organism-specific biosystem (from Pathway Interaction Database)
      Notch signaling pathway, organism-specific biosystem
      Notch signaling pathway
    • Notch signaling pathway, conserved biosystem (from KEGG)
      Notch signaling pathway, conserved biosystemThe Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch pro...
    • Nuclear signaling by ERBB4, organism-specific biosystem (from REACTOME)
      Nuclear signaling by ERBB4, organism-specific biosystemBesides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembr...
    • Presenilin action in Notch and Wnt signaling, organism-specific biosystem (from Pathway Interaction Database)
      Presenilin action in Notch and Wnt signaling, organism-specific biosystem
      Presenilin action in Notch and Wnt signaling
    • Regulated proteolysis of p75NTR, organism-specific biosystem (from REACTOME)
      Regulated proteolysis of p75NTR, organism-specific biosystemp75NTR undergoes a process of regulated intramembrane proteolysis (RIP) similar to other transmembrane proteins such as NOTCH, beta-amyloid precursor protein (APP), and ERBB4. Each of these proteins ...
    • Signal Transduction, organism-specific biosystem (from REACTOME)
      Signal Transduction, organism-specific biosystemSignal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such a...
    • Signaling by ERBB4, organism-specific biosystem (from REACTOME)
      Signaling by ERBB4, organism-specific biosystemERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR i.e. HER1), ERBB2 (HER2 i.e. NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular lig...
    • Signaling by NOTCH, organism-specific biosystem (from REACTOME)
      Signaling by NOTCH, organism-specific biosystemThe Notch Signaling Pathway (NSP) is a highly conserved pathway for cell-cell communication. NSP is involved in the regulation of cellular differentiation, proliferation, and specification. For exam...
    • Signaling by NOTCH1, organism-specific biosystem (from REACTOME)
      Signaling by NOTCH1, organism-specific biosystemNOTCH1 functions as both a transmembrane receptor presented on the cell surface and as a transcriptional regulator in the nucleus.NOTCH1 receptor presented on the plasma membrane is activated by a me...
    • Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer, organism-specific biosystem (from REACTOME)
      Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer, organism-specific biosystemMutations in the heterodimerization domain (HD) and PEST domain of NOTCH1 are frequently found in cis in T-cell acute lymphoblastic leukemia. While HD mutations alone result in up to ~10-fold increas...
    • Signaling by NOTCH1 PEST Domain Mutants in Cancer, organism-specific biosystem (from REACTOME)
      Signaling by NOTCH1 PEST Domain Mutants in Cancer, organism-specific biosystemNOTCH1 PEST domain mutations are frequently found in T-cell acute lymphoblastic leukemia (T-ALL). PEST domain mutations interfere with ubiquitination-mediated NOTCH1 downregulation and result in prol...
    • Signaling by NOTCH1 in Cancer, organism-specific biosystem (from REACTOME)
      Signaling by NOTCH1 in Cancer, organism-specific biosystemHuman NOTCH1 was cloned as a chromosome 9 gene, translocated to the T-cell beta receptor (TCBR) promoter on chromosome 7 in T-cell acute lymphoblastic leukemia (T-ALL) (Ellisen et al. 1991). This tra...
    • Signaling by NOTCH2, organism-specific biosystem (from REACTOME)
      Signaling by NOTCH2, organism-specific biosystemNOTCH2 is activated by binding Delta-like and Jagged ligands (DLL/JAG) expressed in trans on neighboring cells (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004). In trans ...
    • Signaling by NOTCH3, organism-specific biosystem (from REACTOME)
      Signaling by NOTCH3, organism-specific biosystemSimilar to NOTCH1, NOTCH3 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH3, first by ADAM10 at the S2 cleav...
    • Signaling by NOTCH4, organism-specific biosystem (from REACTOME)
      Signaling by NOTCH4, organism-specific biosystemSimilar to NOTCH1, NOTCH4 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH4, first by ADAM10 at the S2 cleav...
    • Signalling by NGF, organism-specific biosystem (from REACTOME)
      Signalling by NGF, organism-specific biosystemNeurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in mi...
    • Syndecan-3-mediated signaling events, organism-specific biosystem (from Pathway Interaction Database)
      Syndecan-3-mediated signaling events, organism-specific biosystem
      Syndecan-3-mediated signaling events
    • p75 NTR receptor-mediated signalling, organism-specific biosystem (from REACTOME)
      p75 NTR receptor-mediated signalling, organism-specific biosystemBesides signalling through the tyrosine kinase receptors TRK A, B, and C, the mature neurotrophins NGF, BDNF, and NT3/4 signal through their common receptor p75NTR. NGF binding to p75NTR activates a ...
    • p75(NTR)-mediated signaling, organism-specific biosystem (from Pathway Interaction Database)
      p75(NTR)-mediated signaling, organism-specific biosystem
      p75(NTR)-mediated signaling
    Products Interactant Other Gene Complex Source Pubs Description

    Markers

    Homology

    Clone Names

    • KIAA0253, RP11-517F10.1

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    endopeptidase activity IEA
    Inferred from Electronic Annotation
    more info
     
    protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    Process Evidence Code Pubs
    Notch receptor processing TAS
    Traceable Author Statement
    more info
    PubMed 
    Notch signaling pathway TAS
    Traceable Author Statement
    more info
     
    T cell proliferation IEA
    Inferred from Electronic Annotation
    more info
     
    amyloid precursor protein catabolic process TAS
    Traceable Author Statement
    more info
    PubMed 
    beta-amyloid metabolic process IEA
    Inferred from Electronic Annotation
    more info
     
    ephrin receptor signaling pathway TAS
    Traceable Author Statement
    more info
     
    epithelial cell proliferation IEA
    Inferred from Electronic Annotation
    more info
     
    membrane protein ectodomain proteolysis IDA
    Inferred from Direct Assay
    more info
    PubMed 
    membrane protein ectodomain proteolysis ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    membrane protein intracellular domain proteolysis TAS
    Traceable Author Statement
    more info
     
    myeloid cell homeostasis IEA
    Inferred from Electronic Annotation
    more info
     
    positive regulation of apoptotic process TAS
    Traceable Author Statement
    more info
     
    positive regulation of catalytic activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    positive regulation of catalytic activity ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    protein processing IDA
    Inferred from Direct Assay
    more info
    PubMed 
    protein processing ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    proteolysis NAS
    Non-traceable Author Statement
    more info
    PubMed 
    Component Evidence Code Pubs
    Golgi apparatus IDA
    Inferred from Direct Assay
    more info
    PubMed 
    Golgi apparatus ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    endoplasmic reticulum IDA
    Inferred from Direct Assay
    more info
    PubMed 
    endoplasmic reticulum ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    extracellular exosome IDA
    Inferred from Direct Assay
    more info
    PubMed 
    focal adhesion IDA
    Inferred from Direct Assay
    more info
    PubMed 
    integral component of membrane NAS
    Non-traceable Author Statement
    more info
    PubMed 
    integral component of plasma membrane IDA
    Inferred from Direct Assay
    more info
    PubMed 
    integral component of plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    lysosomal membrane IDA
    Inferred from Direct Assay
    more info
    PubMed 
    melanosome IEA
    Inferred from Electronic Annotation
    more info
     
    membrane IDA
    Inferred from Direct Assay
    more info
    PubMed 
    plasma membrane TAS
    Traceable Author Statement
    more info
     
    Preferred Names
    nicastrin
    Names
    anterior pharynx-defective 2

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_027935.1 RefSeqGene

      Range
      5001..20680
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001290184.1NP_001277113.1  nicastrin isoform 2

      See identical proteins and their annotated locations for NP_001277113.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) has a different 5' structure resulting in translation initiation at an alternate AUG compared to variant 1; the 5'-most AUG, as used in variant 1, is associated with a truncated ORF that would render the transcript a candidate for nonsense-mediated decay (NMD). Leaky scanning may allow translation initiation at the alternate AUG resulting in a shorter isoform (2) with a distinct N-terminus compared to isoform 1.
      Source sequence(s)
      AF240468, AL445230, BC047621, CN429672
      Consensus CDS
      CCDS76228.1
      UniProtKB/Swiss-Prot
      Q92542
      Related
      ENSP00000357042, OTTHUMP00000031840, ENST00000368063, OTTHUMT00000080623
      Conserved Domains (1) summary
      cd03881
      Location:155462
      M28_Nicastrin; M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex
    2. NM_001290186.1NP_001277115.1  nicastrin isoform 3 precursor

      See identical proteins and their annotated locations for NP_001277115.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks three alternate in-frame exons in the coding region compared to variant 1. The encoded isoform (3) is shorter than isoform 1.
      Source sequence(s)
      AF240468, AK299142, AL445230, CN429672
      UniProtKB/Swiss-Prot
      Q92542
      UniProtKB/TrEMBL
      B4DR82
      Conserved Domains (1) summary
      cl14876
      Location:195361
      Zinc_peptidase_like; Zinc peptidases M18, M20, M28, and M42
    3. NM_015331.2NP_056146.1  nicastrin isoform 1 precursor

      See identical proteins and their annotated locations for NP_056146.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (1).
      Source sequence(s)
      AF240468, BC047621, CN429672
      Consensus CDS
      CCDS1203.1
      UniProtKB/Swiss-Prot
      Q92542
      Related
      ENSP00000294785, OTTHUMP00000031839, ENST00000294785, OTTHUMT00000080622
      Conserved Domains (1) summary
      cd03881
      Location:175482
      M28_Nicastrin; M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex

    RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 108 details...

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p7 Primary Assembly

    Genomic

    1. NC_000001.11 Reference GRCh38.p7 Primary Assembly

      Range
      160343056..160358952
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011509363.2XP_011507665.1  

      Conserved Domains (1) summary
      cd03881
      Location:175482
      M28_Nicastrin; M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex
    2. XM_005245053.4XP_005245110.1  

      Conserved Domains (1) summary
      cd03881
      Location:175395
      M28_Nicastrin; M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex

    Alternate CHM1_1.1

    Genomic

    1. NC_018912.2 Alternate CHM1_1.1

      Range
      161708406..161724081
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)