APPL2 adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2 [Homo sapiens (human)] - Gene

Summary

Official Symbol: APPL2provided by HGNC
Official Full Name: adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2provided by HGNC
Primary source: HGNC:HGNC:18242
See related: Ensembl:ENSG00000136044 MIM:606231; AllianceGenome:HGNC:18242
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
Also known as: DIP13B
Summary: The protein encoded by this gene is one of two effectors of the small GTPase RAB5A/Rab5, which are involved in a signal transduction pathway. Both effectors contain an N-terminal Bin/Amphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain, and a C-terminal phosphotyrosine binding (PTB) domain, and they bind the Rab5 through the BAR domain. They are associated with endosomal membranes and can be translocated to the nucleus in response to the EGF stimulus. They interact with the NuRD/MeCP1 complex (nucleosome remodeling and deacetylase /methyl-CpG-binding protein 1 complex) and are required for efficient cell proliferation. A chromosomal aberration t(12;22)(q24.1;q13.3) involving this gene and the PSAP2 gene results in 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome. [provided by RefSeq, Oct 2011]
Expression: Ubiquitous expression in colon (RPKM 10.8), small intestine (RPKM 10.3) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 12q23.3

Exon count:: 23

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	12	NC_000012.12 (105173300..105236174, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	12	NC_060936.1 (105135121..105197990, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	12	NC_000012.11 (105567078..105629952, complement)

Chromosome 12 - NC_000012.12 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

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic beta-cells.
Title: The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells.
A negative correlation of expression is evident between APPL2 and OCC-1 genes in breast cancer specimen. Unlike OCC-1A/B which encodes a small protein, OCC-1D noncoding RNA overexpression lead to APPL2 downregulation in MCF7 cells.
Title: Overexpressed in colorectal carcinoma gene (OCC-1) upregulation and APPL2 gene downregulation in breast cancer specimens.
Results show the suppressive effect of OCC-1 RNA on transcription level of the APPL2 gene provides a putative colorectal neoplasm progression index.
Title: Alternative splicing of the OCC-1 gene generates three splice variants and a novel exonic microRNA, which regulate the Wnt signaling pathway.
Data show that signal transducing adaptor proteins APPL1 and APPL2 are required for TGFbeta-induced nuclear translocation of TGFbeta type I receptor (TbetaRI)-ICD and for cancer cell invasiveness of prostate and breast cancer cell lines.
Title: APPL proteins promote TGFβ-induced nuclear transport of the TGFβ type I receptor intracellular domain.
ATM is the central modulator of APPL-mediated effects on radiosensitivity and DNA repair.
Title: APPL proteins modulate DNA repair and radiation survival of pancreatic carcinoma cells by regulating ATM.
It concludes that APPL2(PH) binding to BAR domain and Reptin is mutually exclusive which regulates the nucleocytoplasmic shuttling of Reptin.
Title: Mutually exclusive binding of APPL(PH) to BAR domain and Reptin regulates β-catenin dependent transcriptional events.
C-APPL1/A-APPL2 allele combination is associated with non-alcoholic fatty liver disease occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver.
Title: Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.
Data indicate that a high level of APPL2 protein might enhance glioblastoma growth by maintaining low expression level of genes responsible for cell death induction.
Title: Multifunctional protein APPL2 contributes to survival of human glioma cells.
analysis of APPL1 and APPL2 proteins and their interaction with Rab
Title: Membrane curvature protein exhibits interdomain flexibility and binds a small GTPase.
found significant evidence of association with overweight/obesity for rs2272495 and rs1107756. rs2272495 C allele and rs1107756 T allele both conferred a higher risk of being overweight and obese.
Title: Genetic variations in APPL2 are associated with overweight and obesity in a Chinese population with normal glucose tolerance.

Submit: New GeneRIF Correction See all GeneRIFs (16)

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

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

STS-R77239 (e-PCR)
- UniSTS:30217

RH44961 (e-PCR)
- UniSTS:832

SHGC-3540 (e-PCR)
- UniSTS:92485

D12S317 (e-PCR), detects polymorphism
- UniSTS:36448

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables phosphatidylinositol binding	IDA Inferred from Direct Assay more info	PubMed
enables phosphatidylserine binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	IDA Inferred from Direct Assay more info	PubMed
enables protein-containing complex binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
involved_in adiponectin-activated signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in cellular response to hepatocyte growth factor stimulus	ISS Inferred from Sequence or Structural Similarity more info
involved_in cold acclimation	ISS Inferred from Sequence or Structural Similarity more info
involved_in diet induced thermogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in glucose homeostasis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of D-glucose import	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of D-glucose import	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of cellular response to insulin stimulus	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of cytokine production involved in inflammatory response	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of fatty acid oxidation	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of neural precursor cell proliferation	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of neurogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of Fc-gamma receptor signaling pathway involved in phagocytosis	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of cold-induced thermogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of macropinocytosis	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of phagocytosis, engulfment	ISS Inferred from Sequence or Structural Similarity more info
involved_in protein homotetramerization	IDA Inferred from Direct Assay more info	PubMed
involved_in protein import into nucleus	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of G1/S transition of mitotic cell cycle	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of fibroblast migration	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of innate immune response	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of toll-like receptor 4 signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in signal transduction	TAS Traceable Author Statement more info	PubMed
involved_in signaling	IBA Inferred from Biological aspect of Ancestor more info
involved_in transforming growth factor beta receptor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
located_in cytoplasmic vesicle	IDA Inferred from Direct Assay more info	PubMed
located_in early endosome membrane	IEA Inferred from Electronic Annotation more info
located_in early phagosome	ISS Inferred from Sequence or Structural Similarity more info
located_in early phagosome membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in endosome	IDA Inferred from Direct Assay more info	PubMed
is_active_in endosome membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in endosome membrane	IDA Inferred from Direct Assay more info	PubMed
located_in extracellular exosome	HDA more info	PubMed
located_in macropinosome	ISS Inferred from Sequence or Structural Similarity more info
located_in membrane	IDA Inferred from Direct Assay more info	PubMed
located_in nucleus	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in ruffle	ISS Inferred from Sequence or Structural Similarity more info
located_in ruffle membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in vesicle	IDA Inferred from Direct Assay more info	PubMed

General protein information

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Preferred Names: DCC-interacting protein 13-beta

Names: DIP13 beta; adapter protein containing PH domain, PTB domain and leucine zipper motif 2; adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2

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.

Genomic

NG_030419.2 RefSeqGene

Range

5000..67874

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001251904.2 → NP_001238833.1 DCC-interacting protein 13-beta isoform 2

Status: REVIEWED

Description

Transcript Variant: This variant (2) has an additional in-frame segment in the coding region, compared to variant 1. The resulting isoform 2 is longer than isoform 1.

Source sequence(s)

AC016257, AC078874

Consensus CDS

CCDS58276.1

UniProtKB/TrEMBL

A8K3E7

Related

ENSP00000446917.1, ENST00000551662.5

Conserved Domains (3) summary

cd07632
Location:20 → 240

BAR_APPL2; The Bin/Amphiphysin/Rvs (BAR) domain of Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing 2

cd13158
Location:488 → 621

PTB_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain

cd13247
Location:258 → 382

BAR-PH_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain
NM_001251905.2 → NP_001238834.1 DCC-interacting protein 13-beta isoform 3

Status: REVIEWED

Description

Transcript Variant: This variant (3) differs in the 5' exon, which results in a downstream AUG start codon, compared to variant 1. The resulting isoform (3) has a shorter N-terminus, compared to isoform 1.

Source sequence(s)

AC016257, AC078874

Consensus CDS

CCDS58275.1

UniProtKB/TrEMBL

A8K3E7

Related

ENSP00000444472.2, ENST00000539978.6

Conserved Domains (4) summary

cd13158
Location:439 → 572

PTB_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain

cd13247
Location:209 → 333

BAR-PH_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain

pfam00169
Location:235 → 332

PH; PH domain

cl12013
Location:1 → 191

BAR; The Bin/Amphiphysin/Rvs (BAR) domain, a dimerization module that binds membranes and detects membrane curvature
NM_018171.5 → NP_060641.2 DCC-interacting protein 13-beta isoform 1

See identical proteins and their annotated locations for NP_060641.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the predominant isoform (1).

Source sequence(s)

AC016257, AC078874

Consensus CDS

CCDS9101.1

UniProtKB/Swiss-Prot

B7Z411, B7Z4B0, F5GZG0, F8W1P5, Q8N4R7, Q8NEU8, Q9NVL2

UniProtKB/TrEMBL

A8K3E7

Related

ENSP00000258530.3, ENST00000258530.8

Conserved Domains (3) summary

cd07632
Location:20 → 234

BAR_APPL2; The Bin/Amphiphysin/Rvs (BAR) domain of Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing 2

cd13158
Location:482 → 615

PTB_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain

cd13247
Location:252 → 376

BAR-PH_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000012.12 Reference GRCh38.p14 Primary Assembly

Range

105173300..105236174 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_017019554.2 → XP_016875043.1 DCC-interacting protein 13-beta isoform X5

UniProtKB/TrEMBL

A8K3E7
XM_006719472.2 → XP_006719535.1 DCC-interacting protein 13-beta isoform X4

UniProtKB/TrEMBL

A8K3E7

Conserved Domains (4) summary

cd07632
Location:20 → 240

BAR_APPL2; The Bin/Amphiphysin/Rvs (BAR) domain of Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing 2

cd13247
Location:258 → 382

BAR-PH_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain

pfam00169
Location:284 → 381

PH; PH domain

cl17171
Location:488 → 563

PH-like; Pleckstrin homology-like domain
XM_017019551.3 → XP_016875040.1 DCC-interacting protein 13-beta isoform X2

UniProtKB/TrEMBL

A8K3E7
XM_047429065.1 → XP_047285021.1 DCC-interacting protein 13-beta isoform X8
XM_011538532.4 → XP_011536834.1 DCC-interacting protein 13-beta isoform X3

See identical proteins and their annotated locations for XP_011536834.1

UniProtKB/TrEMBL

A8K3E7

Conserved Domains (4) summary

cd13158
Location:445 → 578

PTB_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain

cd13247
Location:215 → 339

BAR-PH_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain

pfam00169
Location:241 → 338

PH; PH domain

cl12013
Location:1 → 197

BAR; The Bin/Amphiphysin/Rvs (BAR) domain, a dimerization module that binds membranes and detects membrane curvature
XM_047429062.1 → XP_047285018.1 DCC-interacting protein 13-beta isoform X3
XM_011538531.4 → XP_011536833.1 DCC-interacting protein 13-beta isoform X3

See identical proteins and their annotated locations for XP_011536833.1

UniProtKB/TrEMBL

A8K3E7

Conserved Domains (4) summary

cd13158
Location:445 → 578

PTB_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain

cd13247
Location:215 → 339

BAR-PH_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain

pfam00169
Location:241 → 338

PH; PH domain

cl12013
Location:1 → 197

BAR; The Bin/Amphiphysin/Rvs (BAR) domain, a dimerization module that binds membranes and detects membrane curvature
XM_047429064.1 → XP_047285020.1 DCC-interacting protein 13-beta isoform X7
XM_047429063.1 → XP_047285019.1 DCC-interacting protein 13-beta isoform X6
XM_011538530.4 → XP_011536832.1 DCC-interacting protein 13-beta isoform X1

UniProtKB/TrEMBL

A8K3E7

Conserved Domains (4) summary

cd07632
Location:7 → 227

BAR_APPL2; The Bin/Amphiphysin/Rvs (BAR) domain of Adaptor protein, Phosphotyrosine interaction, PH domain and Leucine zipper containing 2

cd13158
Location:475 → 608

PTB_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif (APPL; also called DCC-interacting protein (DIP)-13alpha) Phosphotyrosine-binding (PTB) domain

cd13247
Location:245 → 369

BAR-PH_APPL; Adaptor protein containing PH domain, PTB domain, and Leucine zipper motif Bin1/amphiphysin/Rvs167 (BAR)-Pleckstrin homology (PH) domain

pfam00169
Location:271 → 368

PH; PH domain
XM_047429066.1 → XP_047285022.1 DCC-interacting protein 13-beta isoform X9