UniProt functional annotation for Q01705



	UniProt functional annotation for Q01705

UniProt code: Q01705.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

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). {ECO:0000269|PubMed:15965470, ECO:0000269|PubMed:18299578, ECO:0000269|PubMed:23160044, ECO:0000269|PubMed:23615612}.

Subunit: 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. Notch 1 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. 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. 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. 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) (PubMed:28498977). Interacts with DLL1 and JAG1 (PubMed:28089369). Interacts (via NICD domain) with PRAG1 (PubMed:25038227). Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner (PubMed:25038227). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). {ECO:0000250|UniProtKB:P46531, ECO:0000250|UniProtKB:Q07008, ECO:0000269|PubMed:11226752, ECO:0000269|PubMed:12050162, ECO:0000269|PubMed:15019995, ECO:0000269|PubMed:15965470, ECO:0000269|PubMed:17573339, ECO:0000269|PubMed:18299578, ECO:0000269|PubMed:21464124, ECO:0000269|PubMed:23160044, ECO:0000269|PubMed:23615612, ECO:0000269|PubMed:25038227, ECO:0000269|PubMed:28089369, ECO:0000269|PubMed:28498977}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:10882062, ECO:0000269|PubMed:28498977}; Single-pass type I membrane protein.

Subcellular location: [Notch 1 intracellular domain]: Nucleus {ECO:0000269|PubMed:28498977}. Note=Following proteolytical processing NICD is translocated to the nucleus. Nuclear location may require MEGF10. {ECO:0000269|PubMed:28498977}.

Tissue specificity: Highly expressed in the brain, lung and thymus. Expressed at lower levels in the spleen, bone-marrow, spinal cord, eyes, mammary gland, liver, intestine, skeletal muscle, kidney and heart. In the hair follicle, highly expressed exclusively in the epithelial compartment. {ECO:0000269|PubMed:15965470}.

Developmental stage: First detected in the mesoderm at 7.5 dpc By 8.5 dpc highly expressed in presomitic mesoderm, mesenchyme and endothelial cells, while much lower levels are seen in the neuroepithelium. Between 9.5-10.5 dpc expressed at high levels in the neuroepithelium. At 13.5 dpc expressed in the surface ectoderm, eye and developing whisker follicles. Hair follicle matrix cells expression starts as different cell types become distinguishable in the developing follicle. Expression persists throughout the growth phase of the follicle and maintains the same expression profile in the second hair cycle. The cells in the follicle that undergo a phase of high level expression are in transition from mitotic precursors to several discrete, differentiating cell types. Specifically expressed in cerebellar Bergmann glial cells during postnatal development. {ECO:0000269|PubMed:1425352, ECO:0000269|PubMed:1426644, ECO:0000269|PubMed:8486742}.

Domain: Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond. {ECO:0000250|UniProtKB:P46531}.

Ptm: 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 (PubMed:10882062, PubMed:10882063). 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:10882062, PubMed:10882063). 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:10882062, PubMed:11518718, PubMed:11459941). {ECO:0000269|PubMed:10882062, ECO:0000269|PubMed:10882063, ECO:0000269|PubMed:11459941, ECO:0000269|PubMed:11518718}.

Ptm: Phosphorylated.

Ptm: 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) (By similarity). O-glycosylated on the EGF-like domains (PubMed:21757702). 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-glycosylation at Ser-1027 is only partial (PubMed:21757702). 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 (PubMed:28089369). {ECO:0000250|UniProtKB:P46531, ECO:0000250|UniProtKB:Q07008, ECO:0000269|PubMed:21757702, ECO:0000269|PubMed:28089369, ECO:0000269|PubMed:30127001}.

Ptm: Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Monoubiquitination at Lys- 1749 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:15240571). {ECO:0000269|PubMed:15240571, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:23886940}.

Ptm: Hydroxylated at Asn-1945 and Asn-2012 by HIF1AN. Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD. {ECO:0000269|PubMed:17573339, ECO:0000269|PubMed:18299578}.

Similarity: Belongs to the NOTCH family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



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). {ECO:0000269\|PubMed:15965470, ECO:0000269\|PubMed:18299578, ECO:0000269\|PubMed:23160044, ECO:0000269\|PubMed:23615612}.


Subunit:		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. Notch 1 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. 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. 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. 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) (PubMed:28498977). Interacts with DLL1 and JAG1 (PubMed:28089369). Interacts (via NICD domain) with PRAG1 (PubMed:25038227). Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner (PubMed:25038227). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). {ECO:0000250\|UniProtKB:P46531, ECO:0000250\|UniProtKB:Q07008, ECO:0000269\|PubMed:11226752, ECO:0000269\|PubMed:12050162, ECO:0000269\|PubMed:15019995, ECO:0000269\|PubMed:15965470, ECO:0000269\|PubMed:17573339, ECO:0000269\|PubMed:18299578, ECO:0000269\|PubMed:21464124, ECO:0000269\|PubMed:23160044, ECO:0000269\|PubMed:23615612, ECO:0000269\|PubMed:25038227, ECO:0000269\|PubMed:28089369, ECO:0000269\|PubMed:28498977}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:10882062, ECO:0000269\|PubMed:28498977}; Single-pass type I membrane protein.
Subcellular location:		[Notch 1 intracellular domain]: Nucleus {ECO:0000269\|PubMed:28498977}. Note=Following proteolytical processing NICD is translocated to the nucleus. Nuclear location may require MEGF10. {ECO:0000269\|PubMed:28498977}.
Tissue specificity:		Highly expressed in the brain, lung and thymus. Expressed at lower levels in the spleen, bone-marrow, spinal cord, eyes, mammary gland, liver, intestine, skeletal muscle, kidney and heart. In the hair follicle, highly expressed exclusively in the epithelial compartment. {ECO:0000269\|PubMed:15965470}.
Developmental stage:		First detected in the mesoderm at 7.5 dpc By 8.5 dpc highly expressed in presomitic mesoderm, mesenchyme and endothelial cells, while much lower levels are seen in the neuroepithelium. Between 9.5-10.5 dpc expressed at high levels in the neuroepithelium. At 13.5 dpc expressed in the surface ectoderm, eye and developing whisker follicles. Hair follicle matrix cells expression starts as different cell types become distinguishable in the developing follicle. Expression persists throughout the growth phase of the follicle and maintains the same expression profile in the second hair cycle. The cells in the follicle that undergo a phase of high level expression are in transition from mitotic precursors to several discrete, differentiating cell types. Specifically expressed in cerebellar Bergmann glial cells during postnatal development. {ECO:0000269\|PubMed:1425352, ECO:0000269\|PubMed:1426644, ECO:0000269\|PubMed:8486742}.
Domain:		Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond. {ECO:0000250\|UniProtKB:P46531}.
Ptm:		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 (PubMed:10882062, PubMed:10882063). 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:10882062, PubMed:10882063). 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:10882062, PubMed:11518718, PubMed:11459941). {ECO:0000269\|PubMed:10882062, ECO:0000269\|PubMed:10882063, ECO:0000269\|PubMed:11459941, ECO:0000269\|PubMed:11518718}.
Ptm:		Phosphorylated.
Ptm:		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) (By similarity). O-glycosylated on the EGF-like domains (PubMed:21757702). 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-glycosylation at Ser-1027 is only partial (PubMed:21757702). 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 (PubMed:28089369). {ECO:0000250\|UniProtKB:P46531, ECO:0000250\|UniProtKB:Q07008, ECO:0000269\|PubMed:21757702, ECO:0000269\|PubMed:28089369, ECO:0000269\|PubMed:30127001}.
Ptm:		Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Monoubiquitination at Lys- 1749 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:15240571). {ECO:0000269\|PubMed:15240571, ECO:0000269\|PubMed:18628966, ECO:0000269\|PubMed:23886940}.
Ptm:		Hydroxylated at Asn-1945 and Asn-2012 by HIF1AN. Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD. {ECO:0000269\|PubMed:17573339, ECO:0000269\|PubMed:18299578}.
Similarity:		Belongs to the NOTCH family. {ECO:0000305}.