Nicastrin (NCSTN)

Nicastrin (NCST, or NCT), a single-pass membrane glycoprotein that harbors a large extracellular domain, is an essential component of the gamma-secretase complex. Several lines of evidence indicate that the members of these complexes could also contribute to the control of cell death. NCT controls cell death via phosphoinositide 3-kinase/Akt and p53-dependent pathways and that this function remains independent of the activity and molecular integrity of the gamma-secretase complexes. Increasing evidences have shown that Nicastrin/NCSTN plays a crucial role in gamma-cleavage of the amyloid precursor protein (APP). The glycoprotein Nicastrin is an essential component of the gamma-secretase complex, a high molecular weight complex which also contains the presenilin proteins, Aph-1 and Pen-2. The gamma-secretase complex is not only involved in APP processing but also in the processing of an increasing number of other type I integral membrane proteins. As the largest subunit of the gamma-secretase complex, Nicastrin plays a crucial role in its activation. Inhibition of NCSTN demonstrated an altered gamma-cleavage activity, suggesting its potential implication in developing Alzheimer's disease (AD). In addition, Nicastrin can function to maintain epithelial to mesenchymal transition during breast cancer progression. Anti-nicastrin polyclonal and monoclonal antibodies were able to decrease notch1 and vimentin expression and reduced the invasive capacity of breast cancer cells in vitro.

Nicastrin (NCSTN) Related Areas

Signal Transduction>>Notch Signaling Pathway>>Nicastrin/NCSTN

Stem Cell>>Notch Signaling Pathway>>Nicastrin/NCSTN

Nicastrin (NCSTN) Alternative Names

Nicastrin, NCSTN, RP11-517F10.1, APH2, KIAA0253 [Homo sapiens]

Nicastrin, Ncstn, 9430068N19Rik, AA727311, Aph2, D1Dau13e, Kiaa0253, Nct, mKIAA0253 [Mus musculus]

Summaries for Nicastrin (NCSTN)

Entrez Gene summary for NCSTN:

This NCSTN gene encodes a Type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. Nicastrin 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. Alternatively spliced transcript variants have been described, but their full-length nature has not been determined.

OMIM - description for Nicastrin:

Nicastrin is a type-1 transmembrane glycoprotein that forms high molecular mass gamma-secretase complexes with presenilin-1 (PS1) and presenilin-2 (PS2) that are necessary for the endoproteolysis of several type-1 transmembrane proteins, including beta-amyloid precursor protein (beta-APP) and Notch receptor.

Wikipedia summary for Nicastrin:

Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.
Nicastrin (abbreviated NCT) is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processing amyloid precursor protein (APP) to the short Alzheimer's disease-associated peptide amyloid beta. The other proteins in the complex are presenilin, which is the catalytically active component of the complex, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2). Nicastrin itself is not catalytically active, but instead promotes the maturation and proper trafficking of the other proteins in the complex, all of which undergo significant post-translational modification before becoming active in the cell. Nicastrin has also been identified as a regulator of neprilysin, an enzyme involved in the degradation of amyloid beta fragment.

Human Nicastrin (NCSTN) Protein General Information

 

• Protein names: Nicastrin
• Sequence length: 709 AA.
• Induction: Nicastrin is constitutively expressed in neural cells.
• Sequence similarities: Nicastrin belongs to the nicastrin family.
• Subunit structure: Nicastrin is component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist. Nicastrin binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP).
• Subcellular location: Membrane; Single-pass type I membrane protein. Melanosome. Note: Identified by mass spectrometry in melanosome fractions from stage I to stage IV.
• Tissue specificity: Nicastrin is widely expressed.
• Involvement in disease: Defects in Nicastrin are the cause of familial acne inversa type 1 (ACNINV1) [MIM:142690]. A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.

General information above from UniProt

Function for Nicastrin (NCSTN) Protein

UniProtKB:

Nicastrin is essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Nicastrin probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex.

Genatlas:

• Nicastrin modulates presenilin mediated notch/glp-1 signal transduction in C elegans
• Nicastrin is potential modulator of APP beta cleavage by secretase gamma
• Nicastrin is involved in the degradation of amyloid precursor protein to produce beta-amyloid peptides
• Nicastrin is a member of the gamma-secretase complex, playing a role, with PSEN1, APH1A, PSENEN, necessary and sufficient to reconstitute gamma-secretase activity
• Nicastrin is essential component of the gamma secretase (GS) enzyme complex, required for its synthesis and recognition of substrates for proteolytic cleavage
• Nicastrin can function to maintain epithelial to mesenchymal transition during breast cancer progression
• Nicastrin is part of the gamma-secretase complex and potentially involved in substrate recognition and selection

Homology for human Nicastrin (NCSTN)

• ortholog to rattus Ncstn
• ortholog to murine Ncstn

Phenotype Information for Nicastrin (NCSTN)

• Gene/Locus: NCSTN
• Phenotype: Acne inversa, familial, 1

Phenotype Information for Nicastrin from OMIM (Online Mendelian Inheritance in Man)