Aph1a aph1 homolog A, gamma secretase subunit [Mus musculus (house mouse)] - Gene

Summary

Official Symbol: Aph1aprovided by MGI
Official Full Name: aph1 homolog A, gamma secretase subunitprovided by MGI
Primary source: MGI:MGI:2385110
See related: Ensembl:ENSMUSG00000015750 AllianceGenome:MGI:2385110
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Mus musculus
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus
Also known as: APH-1a
Summary: This gene encodes a subunit of the gamma-secretase complex, which is localized to the endoplasmic reticulum and golgi apparatus. Gamma-secretase is a multi-protein enzyme that catalyzes intramembraneous proteolysis of type I transmembrane proteins and is essential for many signaling pathways, including the Notch signaling pathway. Studies suggest that the protein encoded by this locus binds directly to substrates of the gamma-secretase complex, including the beta-amyloid precursor protein which is associated with Alzheimer disease progression. This gene is required for normal embryonic development and survival, and disruption is associated with defects in the yolk sack angiogenesis, neural tube formation, and somitogenesis. A pseudogene of this gene is located on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]
Expression: Ubiquitous expression in duodenum adult (RPKM 104.8), adrenal adult (RPKM 94.8) and 28 other tissues See more
Orthologs: human all
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Genomic context

Location:: 3 F2.1; 3 41.47 cM

Exon count:: 7

Annotation release	Status	Assembly	Chr	Location
RS_2024_02	current	GRCm39 (GCF_000001635.27)	3	NC_000069.7 (95801233..95805904)
108.20200622	previous assembly	GRCm38.p6 (GCF_000001635.26)	3	NC_000069.6 (95893921..95898592)

Chromosome 3 - NC_000069.7 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: Mouse ENCODE transcriptome data
Description: RNA profiling data sets generated by the Mouse ENCODE project.
BioProject: PRJNA66167
Publication: PMID 25409824
Analysis date: n/a

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

We propose a model that identifies critical TMDs of Aph-1 for associations with Nct and PS for the stepwise assembly of gamma-secretase components.
Title: Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin.
Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease.
Title: Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease.
Assembly of gamma-secretase occurs through stable dimers after exit from the endoplasmic reticulum.
Title: Assembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum.
This work provides novel evidence for the role of miRNAs in memory formation and demonstrates the implication of APH1a protein in miRNA processing in the adult brain.
Title: miR-151-5p modulates APH1a expression to participate in contextual fear memory formation.
Prostaglandin I2 accumulation in neuronal cells activates PKA/CREB and JNK/c-Jun signaling pathways by phosphorylation, which results in APH-1alpha/1beta expression.
Title: Prostaglandin I2 upregulates the expression of anterior pharynx-defective-1α and anterior pharynx-defective-1β in amyloid precursor protein/presenilin 1 transgenic mice.
Thus, Leda-1/Pianp is constitutively processed by proprotein convertases, sheddases including MMPs and ADAM10/17 and intramembrane protease gamma-secretase.
Title: Posttranslational proteolytic processing of Leda-1/Pianp involves cleavage by MMPs, ADAM10/17 and gamma-secretase.
Abeta oligomers in the cerebrospinal fluid (CSF) further promoted the expression of APH-1alpha/-1beta (by >2.5-fold), which enhances the gamma-cleavage of APP and Abeta deposition during AD progression
Title: By suppressing the expression of anterior pharynx-defective-1α and -1β and inhibiting the aggregation of β-amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice.
Upregulation of PS1/gamma-secretase activity may be a risk factor for late onset sporadic Alzheimer's disease.
Title: Increased expression of PS1 is sufficient to elevate the level and activity of γ-secretase in vivo.
ficiency of beta-arrestin1 or inhibition of binding of beta-arrestin1 with APH-1 by small peptides reduced Abeta production without affecting Notch processing
Title: β-arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology.
Pen-2, as well as nicastrin and Aph-1alpha, is dispensable for presenilin endoproteolysis
Title: Pen-2 is dispensable for endoproteolysis of presenilin 1, and nicastrin-Aph subcomplex is important for both γ-secretase assembly and substrate recruitment.

Submit: New GeneRIF Correction See all GeneRIFs (14)

Variation

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Alleles

Alleles of this type are documented at Mouse Genome Informatics (MGI)

Endonuclease-mediated (2)
Targeted (7) 1 citation

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

MARC_7139-7140:992008251:1 (e-PCR)
- UniSTS:231303

MARC_7139-7140:996687542:1 (e-PCR)
- UniSTS:231303

AB005450 (e-PCR)
- UniSTS:163316

Gene Ontology Provided by MGI

Function	Evidence Code	Pubs
enables endopeptidase activator activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables endopeptidase activator activity	ISO Inferred from Sequence Orthology more info
enables enzyme binding	IPI Inferred from Physical Interaction more info	PubMed
enables peptidase activity	ISA Inferred from Sequence Alignment more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein-macromolecule adaptor activity	IBA Inferred from Biological aspect of Ancestor more info
enables protein-macromolecule adaptor activity	IEA Inferred from Electronic Annotation more info
enables protein-macromolecule adaptor activity	ISO Inferred from Sequence Orthology more info

Process	Evidence Code	Pubs
involved_in Notch receptor processing	IBA Inferred from Biological aspect of Ancestor more info
acts_upstream_of_or_within Notch receptor processing	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in Notch receptor processing	ISO Inferred from Sequence Orthology more info
involved_in Notch receptor processing	NAS Non-traceable Author Statement more info	PubMed
involved_in Notch signaling pathway	IBA Inferred from Biological aspect of Ancestor more info
involved_in Notch signaling pathway	IEA Inferred from Electronic Annotation more info
involved_in amyloid precursor protein catabolic process	ISO Inferred from Sequence Orthology more info
involved_in amyloid precursor protein catabolic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in amyloid precursor protein metabolic process	ISO Inferred from Sequence Orthology more info
involved_in amyloid-beta formation	IEA Inferred from Electronic Annotation more info
involved_in amyloid-beta formation	ISO Inferred from Sequence Orthology more info
involved_in membrane protein ectodomain proteolysis	ISO Inferred from Sequence Orthology more info
involved_in membrane protein ectodomain proteolysis	ISS Inferred from Sequence or Structural Similarity more info
involved_in membrane protein intracellular domain proteolysis	ISO Inferred from Sequence Orthology more info
involved_in membrane protein intracellular domain proteolysis	ISS Inferred from Sequence or Structural Similarity more info
acts_upstream_of_or_within metanephros development	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of endopeptidase activity	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of endopeptidase activity	ISO Inferred from Sequence Orthology more info
involved_in protein processing	IBA Inferred from Biological aspect of Ancestor more info
acts_upstream_of_or_within protein processing	ISA Inferred from Sequence Alignment more info	PubMed
involved_in protein processing	ISO Inferred from Sequence Orthology more info
involved_in protein processing	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
located_in Golgi apparatus	ISO Inferred from Sequence Orthology more info
located_in Golgi apparatus	ISS Inferred from Sequence or Structural Similarity more info
located_in Golgi cisterna membrane	IEA Inferred from Electronic Annotation more info
located_in Golgi membrane	NAS Non-traceable Author Statement more info	PubMed
located_in early endosome	IEA Inferred from Electronic Annotation more info
located_in early endosome	ISO Inferred from Sequence Orthology more info
is_active_in endoplasmic reticulum	IBA Inferred from Biological aspect of Ancestor more info
located_in endoplasmic reticulum	ISO Inferred from Sequence Orthology more info
located_in endoplasmic reticulum	ISS Inferred from Sequence or Structural Similarity more info
located_in endoplasmic reticulum	NAS Non-traceable Author Statement more info	PubMed
located_in endoplasmic reticulum membrane	NAS Non-traceable Author Statement more info	PubMed
part_of gamma-secretase complex	IBA Inferred from Biological aspect of Ancestor more info
part_of gamma-secretase complex	ISO Inferred from Sequence Orthology more info
part_of gamma-secretase complex	ISS Inferred from Sequence or Structural Similarity more info
located_in membrane	ISA Inferred from Sequence Alignment more info	PubMed
located_in membrane	ISO Inferred from Sequence Orthology more info
located_in plasma membrane	ISO Inferred from Sequence Orthology more info
located_in plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in plasma membrane	TAS Traceable Author Statement more info
located_in presynaptic membrane	IEA Inferred from Electronic Annotation more info
is_active_in presynaptic membrane	ISO Inferred from Sequence Orthology more info
located_in synaptic membrane	ISO Inferred from Sequence Orthology more info
located_in synaptic vesicle	IEA Inferred from Electronic Annotation more info
located_in synaptic vesicle	ISO Inferred from Sequence Orthology more info

General protein information

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Preferred Names: gamma-secretase subunit APH-1A

Names: anterior pharynx defective 1a homolog; aph-1alpha

NCBI Reference Sequences (RefSeq)

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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.

mRNA and Protein(s)

NM_146104.3 → NP_666216.1 gamma-secretase subunit APH-1A isoform 1

See identical proteins and their annotated locations for NP_666216.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) differs in the 3' coding region and 3' UTR, compared to variant 2. The resulting isoform (1, also known as isoform S) is shorter and has a distinct C-terminus, compared to isoform 2.

Source sequence(s)

AC092855, AK148400, BY264531

Consensus CDS

CCDS17624.1

UniProtKB/TrEMBL

Q3U886, Q6GTF1

Related

ENSMUSP00000015894.6, ENSMUST00000015894.12

Conserved Domains (1) summary

pfam06105
Location:3 → 233

Aph-1; Aph-1 protein
NM_146134.2 → NP_666246.1 gamma-secretase subunit APH-1A isoform 2

See identical proteins and their annotated locations for NP_666246.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) encodes the longer isoform (2, also known as isoform L).

Source sequence(s)

AC092855, AK148400, BY264531, CX207467

Consensus CDS

CCDS50999.1

UniProtKB/Swiss-Prot

Q8BVF7, Q8R1T3, Q91VL5

UniProtKB/TrEMBL

Q3U886

Related

ENSMUSP00000058846.9, ENSMUST00000056710.10

Conserved Domains (1) summary

pfam06105
Location:3 → 233

Aph-1; Aph-1 protein