NOTCH signalointitien geeneistä ja proteiineista NOTCH1(9q34.3), Neurogenic locus notch homolog protein 1

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 NOTCH1 (9q34.3) , NOTCH reseptori 1

https://www.ncbi.nlm.nih.gov/gene/4851#gene-expression

Also known as

hN1; AOS5; TAN1; AOVD1

Summary

This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

Expression

Ubiquitous expression in fat (RPKM 9.4), spleen (RPKM 9.4) and 25 other tissues See more

 GENECARDS: NOTCH1

NCBI Gene Summary for NOTCH1 Gene

• This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

CIViC Summary for NOTCH1 Gene

• NOTCH1 is one of four known genes encoding the NOTCH family of proteins, a group of receptors involved in the Notch signaling pathway. NOTCH proteins are characterized by N-terminal EGF-like repeats followed by LNR domains which form a complex with ligands to prevent signaling. The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. Activation of Notch has been shown to be correlative with mammary tumorgenesis in mice and increased expression of Notch receptors has been observed in a variety of cancer types including cervical, colon, head and neck, lung, renal, pancreatic, leukemia, and breast cancer. A number of treatment modalities have been explored related to Notch inhibition especially in breast cancer with mixed results.

  GeneCards Summary for NOTCH1 Gene

  NOTCH1 (Notch Receptor 1) is a Protein Coding gene. Diseases associated with NOTCH1 include Aortic Valve Disease 1 and Adams-Oliver Syndrome 5. Among its related pathways are Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants and Pre-NOTCH Expression and Processing. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and sequence-specific DNA binding. An important paralog of this gene is NOTCH2.

  UniProtKB/Swiss-Prot Summary for NOTCH1 Gene

  Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO). ( NOTC1_HUMAN,P46531 ) 

  Protein attributes for NOTCH1 Gene

  Size: 2555 amino acids

  Molecular mass: 272505 Da

  Quaternary structure:

  
  

  • Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds.
    Interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH.
    Also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1 (PubMed:11101851, 12370315).
    The NOTCH1 intracellular domain interacts with SNW1; the interaction involves multimerized NOTCH1 NICD and is implicated in a formation of an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ (PubMed:10713164).
    The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization.
    Forms a trimeric complex with FBXW7 and SGK1.
    Interacts with HIF1AN.
    HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation (PubMed:17573339).
    Interacts (via NICD) with SNAI1 (via zinc fingers); the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion.
    Interacts (via NICD) with MDM2A.
    Interacts (via NICD) with BCL6; the interaction decreases MAML1 recruitment by NOTCH1 NICD on target genes DNA and inhibits NOTCH1 transcractivation activity.
    Interacts with THBS4 (By similarity).
    Interacts (via the EGF-like repeat region) with CCN3 (via CTCK domain) (PubMed:12050162).
    Interacts (via EGF-like domains) with DLL4 (via N-terminal DSL and MNNL domains) (By similarity).
    Interacts with ZMIZ1.
    Interacts (via NICD domain) with MEGF10 (via the cytoplasmic domain).
    Interacts with DLL1 and JAG1 (By similarity).
    Interacts (via NICD domain) with PRAG1 (By similarity).
    Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner (By similarity).
    Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30598546).
    Interacts with ZFP64 (By similarity).

  Post-translational modifications for NOTCH1 Gene

  • Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form (By similarity).
    Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC).
    Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:24226769).
    Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane (PubMed:30598546).
    ( P46531-NOTC1_HUMAN )
  • Phosphorylated. ( P46531-NOTC1_HUMAN )
  • O-glycosylated on the EGF-like domains (PubMed:24226769).
    O-glucosylated at Ser-435 by KDELC1 and KDELC2 (PubMed:30127001).
    Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (By similarity).
    O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (PubMed:24226769).
    MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity).
    ( P46531-NOTC1_HUMAN )
  • Ubiquitinated.
    Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, 23886940).
    Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it.
    Deubiquitination by EIF3F is necessary for nuclear import of activated Notch (PubMed:24226769).
    ( P46531-NOTC1_HUMAN )
  • Hydroxylated at Asn-1955 by HIF1AN.
    Hydroxylated at Asn-2022 by HIF1AN (By similarity).
    Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).
    ( P46531-NOTC1_HUMAN )
  • Glycosylation at Asn41, Ser65, Thr73, Thr116, Ser146, Thr194, Thr232, Thr311, Ser341, Thr349, Ser378, Ser435, Ser458, Thr466, Ser496, Ser534, Ser609, Thr617, Ser647, Thr692, Ser722, Ser759, Thr767, Ser784, Ser797, Thr805, Ser921, Ser951, Asn959, Thr997, Ser1027, Thr1035, Ser1065, Thr1159, Asn1179, Ser1189, Thr1197, Asn1241, Ser1273, Thr1362, Thr1379, Thr1402, Asn1489, Asn1587, and Thr1725 ( NX_P46531 [NX_P46531-1] )
  • Ubiquitination at Lys1759 ( NX_P46531 [NX_P46531-1] )
  • Modification sites at PhosphoSitePlus ( P46531 )
  • Glycosylation from GlyGen (P46531) 57 sites, 3 O-linked glycans (13 sites)

   

  Gene Families for NOTCH1 Gene

  HGNC:

  • Notch receptors
  • MicroRNA protein coding host genes

  IUPHAR :

  • Notch receptors

  Human Protein Atlas (HPA):

  • Cancer-related genes
  • Disease related genes
  • Human disease related genes
  • Plasma proteins
  • Potential drug targets
  • Predicted membrane proteins
  • Transporters

  Protein Domains for NOTCH1 Gene

  InterPro:

  • Ankyrin_rpt
  • Ankyrin_rpt-contain_sf
  • EGF-like_dom
  • EGF-like_Ca-bd_dom
  • EGF-type_Asp/Asn_hydroxyl_site
  • See all 15 »

    InterPro:

    • EGF_Ca-bd_CS
    • Growth_fac_rcpt_cys_sf
    • EGF-like_CS
    • Notch-like_dom_sf
    • Notch_dom
    • Notch
    • Notch_1
    • Notch_C
    • Notch_NOD_dom
    • Notch_NODP_dom

  Blocks:

  • Ankyrin repeat signature
  • Aspartic acid and asparagine hydroxylation site
  • EGF-like calcium-binding
  • LIN-12/notch repeat (LNR) signature

   

  Suggested Antigen Peptide Sequences for NOTCH1 Gene

  GenScript: Design optimal peptide antigens:

  • Truncated NOTCH1 (A7TW83_HUMAN)
  • Translocation-associated notch protein TAN-1 (NOTC1_HUMAN)
  • NOTCH1 protein (Q6IAD4_HUMAN)

  Graphical View of Domain Structure for InterPro Entry

  P46531

  UniProtKB/Swiss-Prot:

  NOTC1_HUMAN :

  • Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.
  • Belongs to the NOTCH family.

  Domain:

  • Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.

  Family:

  • Belongs to the NOTCH family. 

  Molecular function for NOTCH1 Gene according to UniProtKB/Swiss-Prot

  Repetition:  Function:

  • Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.
    Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus.
    Affects the implementation of differentiation, proliferation and apoptotic programs.
    Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting.
    Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus.
    Important for follicular differentiation and possibly cell fate selection within the follicle.
    During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia.
    Represses neuronal and myogenic differentiation.
    May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation.
    May be involved in mesoderm development, somite formation and neurogenesis.
    May enhance HIF1A function by sequestering HIF1AN away from HIF1A.
    Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury.
    Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO). NOTC1_HUMAN,P46531

  Molecular function for NOTCH1 Gene according to GENATLAS

  Biochemistry:

  • Drosophila Notch homolog 1,mediating cell-cell interactions that specify cell fate during development,undergoing a first proteolytic cleavage by furin (PACE1) in the Golgi during trafficking of Notch to the cell surface,undergoing further cleavage by gamma secretase (see PSEN1) releasing an intracellular domain (NICD) which translocates to the nucleus and modulates transcription of target genes,involved in acute lymphocytic leukemia with translocation t(7;9)(q34;q34.3),expressed in CD34+ hematopoietic cells (see TAN1) and in the developing cochlear duct,inducing delay of hematopoietic differentiation and alteration of cell cycle kinetics NOTCH1
  • breakpoint in T acute lymphocytic leukemia with translocation t(7;9)(q34;q34.3) NOTCH1

   https://pathway-viewer.toolforge.org/embed/WP4262

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