AAK1 AP2 associated kinase 1 [Homo sapiens (human)] - Gene

Summary

Official Symbol: AAK1provided by HGNC
Official Full Name: AP2 associated kinase 1provided by HGNC
Primary source: HGNC:HGNC:19679
See related: Ensembl:ENSG00000115977 MIM:616405; AllianceGenome:HGNC:19679
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Summary: This gene encodes a member of the SNF1 subfamily of serine/threonine protein kinases. Adaptor-related protein complex 2 (AP-2 complexes) functions during receptor-mediated endocytosis to trigger clathrin assembly, interact with membrane-bound receptors, and recruit encodytic accessory factors. The encoded protein interacts with and phosphorylates a subunit of the AP-2 complex, which promotes binding of AP-2 to sorting signals found in membrane-bound receptors and subsequent receptor endocytosis. Its kinase activity is stimulated by clathrin. This kinase has been shown to play an important role in regulating the clathrin-mediated endocytosis of the rabies virus, facilitating infection. Inhibitors of this kinase are being studied as candidate therapeutics to disrupt the entry of viruses, including SARS-CoV-2, into target cells. It is also involved in positive regulation of Notch pathway signaling in mammals. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Aug 2020]
Annotation information: Note: This gene has been reviewed for its involvement in coronavirus biology, and is involved in SARS-CoV-2 infection.
Expression: Ubiquitous expression in brain (RPKM 7.8), thyroid (RPKM 4.9) and 24 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 2p13.3

Exon count:: 22

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	2	NC_000002.12 (69457997..69643739, complement)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	2	NC_060926.1 (69470304..69656050, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (69685129..69870871, complement)

Chromosome 2 - NC_000002.12 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

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Extracellular vesicle-transmitted miR-671-5p alleviates lung inflammation and injury by regulating the AAK1/NF-kappaB axis.
Title: Extracellular vesicle-transmitted miR-671-5p alleviates lung inflammation and injury by regulating the AAK1/NF-κB axis.
The Serine/Threonine Kinase AP2-Associated Kinase 1 Plays an Important Role in Rabies Virus Entry.
Title: The Serine/Threonine Kinase AP2-Associated Kinase 1 Plays an Important Role in Rabies Virus Entry.
Author show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway.
Title: WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop.
Results present the first structures of AAK1 and BIKE which reveal that all members of the Numb-associated kinase family share unusual activation segment architecture.
Title: Family-wide Structural Analysis of Human Numb-Associated Protein Kinases.
Two of these kinases that were classified as resistors were PX domain-containing serine/threonine kinase (PXK) and AP2-associated kinase 1 (AAK1), which promote receptor endocytosis and may enable cells to resist TRAIL-induced apoptosis
Title: Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.
AAK1 and GAK are critical regulators of HCV entry that function in part by activating EGFR, AP2M1, and NUMB, and as the molecular targets underlying the antiviral effect of sunitinib and erlotinib, respectively.
Title: AP-2-associated protein kinase 1 and cyclin G-associated kinase regulate hepatitis C virus entry and are potential drug targets.
AAK1 increases the localization of activated Notch to Rab5-positive endocytic vesicles, while AAK1 depletion or overexpression of Numb, an inhibitor of the pathway, interferes with this localization.
Title: The adaptor-associated kinase 1, AAK1, is a positive regulator of the Notch pathway.
Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator)
Title: Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.
Observational study, meta-analysis, and genome-wide association study of gene-disease association. (HuGE Navigator)
Title: Genomewide association study for onset age in Parkinson disease.
These observations suggest that AAK1 functions at multiple steps of the endosomal pathway by regulating transferrin internalization and its rapid recycling back to the plasma membrane from early/sorting endosome.
Title: A novel AAK1 splice variant functions at multiple steps of the endocytic pathway.

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Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
Genetic Variants Associated with Serum Thyroid Stimulating Hormone (TSH) Levels in European Americans and African Americans from the eMERGE Network. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study of a heart failure related metabolomic profile among African Americans in the Atherosclerosis Risk in Communities (ARIC) study. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genomewide association study for onset age in Parkinson disease. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Replication interactions

Interaction	Pubs
Knockdown of AP2 associated kinase 1 (AAK1) by siRNA inhibits HIV-1 replication in HeLa P4/R5 cells	PubMed

Protein interactions

Protein	Gene	Interaction	Pubs
Nef	nef	Genome-wide shRNA screening identifies AAK1, which is required for HIV-1 Nef-induced downregulation of CD4 in HeLa CD4+ cells	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

WI-13642 (e-PCR)
- UniSTS:65295

RH36415 (e-PCR)
- UniSTS:82462

SHGC-57083 (e-PCR)
- UniSTS:44840

L17705 (e-PCR)
- UniSTS:66091

D2S2152 (e-PCR), detects polymorphism
- UniSTS:82480

D8S2279 (e-PCR)
- UniSTS:473907

SHGC-34639 (e-PCR)
- UniSTS:77885

WI-21193 (e-PCR)
- UniSTS:75103

RH81048 (e-PCR)
- UniSTS:87138

D2S420E (e-PCR)
- UniSTS:473193

D10S16 (e-PCR)
- UniSTS:155756

A004N37 (e-PCR)
- UniSTS:41837

D1S1423 (e-PCR)
- UniSTS:149619

RH120335 (e-PCR)
- UniSTS:132475

RH36905 (e-PCR)
- UniSTS:87932

D2S1849 (e-PCR)
- UniSTS:7805

GDB:315881 (e-PCR)
- UniSTS:156545

RH102060 (e-PCR)
- UniSTS:96394

G60358 (e-PCR)
- UniSTS:137614

G62536 (e-PCR)
- UniSTS:139664

RH69534 (e-PCR)
- UniSTS:85402

D2S1631E (e-PCR)
- UniSTS:150693

HSC280_(HIRIPrep1) (e-PCR)
- UniSTS:275884

GDB:631802 (e-PCR)
- UniSTS:158429

D2S1874 (e-PCR)
- UniSTS:153566

GDB:313505 (e-PCR)
- UniSTS:40160

D3S1674 (e-PCR)
- UniSTS:148451

Clone Names

FLJ23712, FLJ25931, FLJ31060, FLJ42882, FLJ45252, KIAA1048, MGC138170, MGC164568, MGC164570, DKFZp686F03202, DKFZp686K16132

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables AP-2 adaptor complex binding	IBA Inferred from Biological aspect of Ancestor more info
enables AP-2 adaptor complex binding	IDA Inferred from Direct Assay more info	PubMed
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables Notch binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein serine kinase activity	IEA Inferred from Electronic Annotation more info
enables protein serine/threonine kinase activity	IBA Inferred from Biological aspect of Ancestor more info
enables protein serine/threonine kinase activity	ISS Inferred from Sequence or Structural Similarity more info
enables protein serine/threonine kinase activity	TAS Traceable Author Statement more info

Process	Evidence Code	Pubs
involved_in membrane organization	TAS Traceable Author Statement more info
involved_in positive regulation of Notch signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in presynaptic endocytosis	IEA Inferred from Electronic Annotation more info
involved_in protein phosphorylation	IBA Inferred from Biological aspect of Ancestor more info
involved_in protein phosphorylation	IDA Inferred from Direct Assay more info	PubMed
involved_in protein stabilization	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of clathrin-dependent endocytosis	IBA Inferred from Biological aspect of Ancestor more info
involved_in regulation of clathrin-dependent endocytosis	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of clathrin-dependent endocytosis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of protein localization	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
located_in cell leading edge	ISS Inferred from Sequence or Structural Similarity more info
located_in clathrin-coated pit	ISS Inferred from Sequence or Structural Similarity more info
located_in clathrin-coated vesicle	ISS Inferred from Sequence or Structural Similarity more info
located_in cytosol	IDA Inferred from Direct Assay more info
located_in cytosol	TAS Traceable Author Statement more info
located_in intracellular membrane-bounded organelle	IDA Inferred from Direct Assay more info
located_in plasma membrane	IDA Inferred from Direct Assay more info
is_active_in presynapse	IBA Inferred from Biological aspect of Ancestor more info
located_in terminal bouton	ISS Inferred from Sequence or Structural Similarity more info

General protein information

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Preferred Names: AP2-associated protein kinase 1

Names: adaptor-associated kinase 1; alternative protein AAK1

NP_001358504.1

EC 2.7.11.1

NP_001358506.1

EC 2.7.11.1

NP_055726.4

EC 2.7.11.1

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_001371575.1 → NP_001358504.1 AP2-associated protein kinase 1 isoform 2

Status: REVIEWED

Source sequence(s)

AC079121, AC092431, AC114772, AC136007

UniProtKB/TrEMBL

B7ZLC4

Related

ENSP00000385181.3, ENST00000406297.7

Conserved Domains (2) summary

PHA03378
Location:296 → 461

PHA03378; EBNA-3B; Provisional

cd14037
Location:42 → 316

STKc_NAK_like; Catalytic domain of Numb-Associated Kinase (NAK)-like Serine/Threonine kinases
NM_001371577.1 → NP_001358506.1 AP2-associated protein kinase 1 isoform 3

Status: REVIEWED

Source sequence(s)

AC079121, AC092431, AC114772

UniProtKB/TrEMBL

E9PG46

Related

ENSP00000386342.1, ENST00000409068.5

Conserved Domains (2) summary

PHA03378
Location:296 → 461

PHA03378; EBNA-3B; Provisional

cd14037
Location:42 → 316

STKc_NAK_like; Catalytic domain of Numb-Associated Kinase (NAK)-like Serine/Threonine kinases
NM_001426745.1 → NP_001413674.1 AP2-associated protein kinase 1 isoform 4

Status: REVIEWED

Source sequence(s)

AC079121, AC092431, AC114772
NM_001426746.1 → NP_001413675.1 AP2-associated protein kinase 1 isoform 5

Status: REVIEWED

Source sequence(s)

AC079121, AC092431, AC114772
NM_014911.5 → NP_055726.4 AP2-associated protein kinase 1 isoform 1

Status: REVIEWED

Source sequence(s)

AC079121, AC114772, AC136007, AW451954, AW969393, BC111965, CA436375, DA121999, DB285703

Consensus CDS

CCDS1893.2

UniProtKB/Swiss-Prot

Q2M2I8, Q4ZFZ3, Q53RX6, Q9UPV4

UniProtKB/TrEMBL

B7ZLC4

Related

ENSP00000386456.3, ENST00000409085.9

Conserved Domains (2) summary

PHA03378
Location:296 → 461

PHA03378; EBNA-3B; Provisional

cd14037
Location:42 → 316

STKc_NAK_like; Catalytic domain of Numb-Associated Kinase (NAK)-like Serine/Threonine kinases