ID:NOTC4_HUMAN DESCRIPTION: RecName: Full=Neurogenic locus notch homolog protein 4; Short=Notch 4; Short=hNotch4; Contains: RecName: Full=Notch 4 extracellular truncation; Contains: RecName: Full=Notch 4 intracellular domain; Flags: Precursor; FUNCTION: Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 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. May regulate branching morphogenesis in the developing vascular system (By similarity). SUBUNIT: Heterodimer of a C-terminal fragment N(TM) and a N- terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH4. SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. SUBCELLULAR LOCATION: Notch 4 intracellular domain: Nucleus. Note=Following proteolytical processing NICD is translocated to the nucleus. TISSUE SPECIFICITY: Highly expressed in the heart, moderately in the lung and placenta and at low levels in the liver, skeletal muscle, kidney, pancreas, spleen, lymph node, thymus, bone marrow and fetal liver. No expression was seen in adult brain or peripheral blood leukocytes. 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. Cleavage results in a C- terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (By similarity). PTM: Phosphorylated (By similarity). POLYMORPHISM: The poly-Leu region of NOTCH4 (in the signal peptide) is polymorphic and the number of Leu varies in the population (from 6 to 12). SIMILARITY: Belongs to the NOTCH family. SIMILARITY: Contains 5 ANK repeats. SIMILARITY: Contains 28 EGF-like domains. SIMILARITY: Contains 3 LNR (Lin/Notch) repeats. SEQUENCE CAUTION: Sequence=BAA09708.1; Type=Frameshift; Positions=1438, 1463;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q99466
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
AJ243937 - Homo sapiens mRNA for G18.1a and G18.1b proteins (G18.1a and G18.1b genes, located in the class III region of the major histocompatibility complex). BC033869 - Homo sapiens Notch homolog 4 (Drosophila), mRNA (cDNA clone IMAGE:5204956), with apparent retained intron. AK131314 - Homo sapiens cDNA FLJ16302 fis, clone PLACE7000502, highly similar to Human Notch4 (hNotch4) mRNA. D63395 - Homo sapiens NOTCH4 mRNA for notch related protein, partial cds. JD096804 - Sequence 77828 from Patent EP1572962. BC140782 - Homo sapiens Notch homolog 4 (Drosophila), mRNA (cDNA clone MGC:176459 IMAGE:9021650), complete cds. BC144540 - Homo sapiens cDNA clone IMAGE:9053067. BC144541 - Homo sapiens cDNA clone IMAGE:9053068. JD434054 - Sequence 415078 from Patent EP1572962. JD412104 - Sequence 393128 from Patent EP1572962. JD553623 - Sequence 534647 from Patent EP1572962. JD245140 - Sequence 226164 from Patent EP1572962. JD234476 - Sequence 215500 from Patent EP1572962. JD302588 - Sequence 283612 from Patent EP1572962. JD179148 - Sequence 160172 from Patent EP1572962. JD371672 - Sequence 352696 from Patent EP1572962. JD119934 - Sequence 100958 from Patent EP1572962. U95299 - Human Notch4 (hNotch4) mRNA, complete cds. AK294161 - Homo sapiens cDNA FLJ57267 complete cds, highly similar to Neurogenic locus notch homolog protein 4 precursor. AK293692 - Homo sapiens cDNA FLJ59128 complete cds, highly similar to Neurogenic locus notch homolog protein 4 precursor. BC063815 - Homo sapiens Notch homolog 4 (Drosophila), mRNA (cDNA clone IMAGE:6180034), complete cds. AK290785 - Homo sapiens cDNA FLJ77085 complete cds, highly similar to Homo sapiens Notch homolog 4 (Drosophila), mRNA. JD465388 - Sequence 446412 from Patent EP1572962. JD498208 - Sequence 479232 from Patent EP1572962. JD476019 - Sequence 457043 from Patent EP1572962. JD068654 - Sequence 49678 from Patent EP1572962. JD186885 - Sequence 167909 from Patent EP1572962.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein Q99466 (Reactome details) participates in the following event(s):
R-HSA-157648 NEXT4 is cleaved to produce NICD4 R-HSA-157941 NICD4 traffics to the nucleus R-HSA-157649 Notch 4-ligand complex is cleaved to produce NEXT4 R-HSA-1912349 Fucosylation of Pre-NOTCH by POFUT1 R-HSA-157633 Notch 4 heterodimer binds with a Notch ligand in the extracellular space R-HSA-212356 Formation of CSL-NICD coactivator complex R-HSA-1912353 Glucosylation of Pre-NOTCH by POGLUT1 R-HSA-1912355 Glycosylation of Pre-NOTCH by FRINGE R-HSA-1912369 NOTCH precursor cleaved to form mature NOTCH R-HSA-1912378 Sialylation of Pre-NOTCH R-HSA-1912352 Galactosylation of Pre-NOTCH R-HSA-1912372 Fringe-modified Pre-NOTCH is cleaved by FURIN R-HSA-1912408 Pre-NOTCH Transcription and Translation R-HSA-157212 A third proteolytic cleavage releases NICD R-HSA-1980150 Signaling by NOTCH4 R-HSA-157052 NICD traffics to nucleus R-HSA-156988 Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor R-HSA-1912399 Pre-NOTCH Processing in the Endoplasmic Reticulum R-HSA-1912422 Pre-NOTCH Expression and Processing R-HSA-157118 Signaling by NOTCH R-HSA-350054 Notch-HLH transcription pathway R-HSA-1912420 Pre-NOTCH Processing in Golgi R-HSA-5083630 Defective LFNG causes SCDO3 R-HSA-162582 Signal Transduction R-HSA-212436 Generic Transcription Pathway R-HSA-3906995 Diseases associated with O-glycosylation of proteins R-HSA-73857 RNA Polymerase II Transcription R-HSA-3781865 Diseases of glycosylation R-HSA-74160 Gene expression (Transcription) R-HSA-1643685 Disease
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
