DAB2 (disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila))

2009-05-01   Maurizio Orlandini 

Department of Molecular Biology, Via Fiorentina 1, 53100 - Siena, Italy

Identity

HGNC
LOCATION
5p13.1
LOCUSID
ALIAS
DOC-2,DOC2
FUSION GENES

DNA/RNA

Description

The DAB2 gene consists of 15 exons and 14 introns spanning in a region of 35 kb in size.

Transcription

The putative DAB2 promoter was identified within a 420-bp sequence upstream of the exon1/intron1 junction. DAB2 is alternatively spliced to generate several transcripts and proteins. The transcript has been detected in spleen, thymus, prostate, testis, small intestine, and abundant in ovary.

Proteins

Note

DAB2 plays a pivotal role in the control of cellular homeostasis. The adaptor protein DAB2 is implicated in several receptor-mediated signaling pathways, endocytosis, cell adhesive function, hematopoietic cell differentiation, and angiogenesis.
Atlas Image
Schematic representation of DAB2 domains. DAB2 possess a highly conserved N-terminal phosphotyrosine-interacting/phosphotyrosine binding domain (PID/PTB), renamed the DAB homology domain, and a C-terminal proline-rich domain (PRD).

Description

770 amino acids, molecular weight 82.5 kDa. DAB2 contains an N-terminal PID/PTB domain (amino acid 42-180) and three C-terminal proline-rich domains (amino acid 619-627, 663-671, and 714-722). A potential actin-binding motif, KKEK is present in the N-terminal domain.

Expression

Widely expressed. Cytoplasmic. DAB2 is expressed in many epithelial cell types and was suggested to have a role in epithelial organization. dab2 knock-out mice are embryonic lethal for defective visceral endoderm cell organization. In fact, in dab2 (-/-) mice, the epithelial cells of the early embryos (visceral endoderm) mix within the interior rather then align as a layer covering the inner cell mass. The role of Dab2 in mediating directional trafficking of endocytic proteins to establish apical polarity is suggested as a mechanism for surface positioning of endoderm cells.

Function

The PID/PTB and PRD domains of DAB2 associate with several proteins, and these interactions have been shown to modulate protein trafficking, cytoskeleton organization, cell adhesion and migration, and cell signaling of various receptor protein-tyrosine kinases.

  • Cell cycle: DAB2 was identified as a protein phosphorylated in response to mitogenic stimulation by CSF-1. In cells, protein phosphorylation of DAB2 modulates its functional activity. Protein kinase C (PKC) and Cdc2 are the two known DAB2 kinases. The major PKC phosphorylation site has been mapped to Ser24 and it is essential for the inhibitory function of DAB2 in TPA-induced AP-1 gene transcription. DAB2 is differentially phosphorylated during the cell cycle by cdc2, and its phosphorylation promotes the association of DAB2 with Pin1, that regulates the rate of DAB2 dephosphorylation.

  • Vesicle traffic: DAB2 plays a role in linking specific extracellular receptors to the endocytic machinery. DAB2 associates with AP-2-positive clathrin-coated structures, together with endocytosed trans-membrane proteins such as low-density lipoprotein (LDL) receptors and integrins. DAB2 also binds to the actin-based myosin VI, mediating the attachment of cargos to motor proteins and regulating protein trafficking.

  • Signaling pathways:
    - TGFbeta - Dab2 associates with Smad2 and Smad3, by a direct interaction with the PID/PTB domain of Dab2, and with TGFbeta receptor I and TGFbeta receptor II. Thus Dab2 may be an essential component of the TGFbeta signaling pathway allowing the transmission of signals from the TGFbeta receptors to the Smad family of transcriptional activators.
    - WNT - Dab2 associates with Axin and stabilizes its expression by preventing Axin interaction with the LRP5 co-receptor. Thus the interaction of Axin with beta-catenin results stabilized with an increase in beta-catenin degradation and attenuation of Wnt signaling.
    - RAS/RAF/MAPK - In cell culture experiments, a Dab2 over-expression leads to suppression of c-Fos expression and cell growth inhibition without affecting MAPK activity. In vivo studies confirmed a Dab2 role in regulating c-Fos expression. A possible molecular mechanism of action is that Dab2 limits the entry of the activated MAPK into the nucleus. DAB2 can also interact with Grb2 through its PRD. Receptor tyrosine kinase activation by growth factors increases the binding of DAB2 to Grb2, which interrupts the binding of SOS to Grb2 and leads to suppression of ERK activation.

  • Cell adhesion: DAB2 is an adhesion-responsive phosphoprotein and plays a role in cell adhesion and spreading. Ser24 phosphorylation promotes membrane translocation of DAB2 and its interaction with beta3 integrin. DAB2 negatively regulates integrin alphaIIbbeta3 activation, leading to the inhibition of alphaIIbbeta3-mediated fibrinogen adhesion. In cell experiments during TGFbeta-induced epithelial to mesenchymal trans-differentiation (EMT), Dab2 expression is increased and Dab2 binds to beta1 integrin. In these conditions, Dab2 silencing leads to a decrease in cell adherence, inhibition of EMT, and apoptosis.
  • Angiogenesis: DAB2 can bind to Shc3 domain of Src and this interaction results in Src inactivation. DAB2 is expressed in human umbilical vein endothelial cells (HUVEC). By modulating the activation of Src-FAK signaling and MAPK phosphorylation, DAB2 controls endothelial cell migration and differentiation.
  • Homology

    The Disabled proteins are a family of adapters involved in cellular signaling, oncogenesis, and development. DAB2 is related to Drosophila Disabled and mammalian Dab1, which regulate neuronal development. DAB2 shares 81% identity with the mouse p96/Dab2 protein.

    Implicated in

    Entity name
    Epithelial ovarian cancer
    Note
    DAB2 was identified due to the loss of its expression in ovarian cancer cells. Ovarian carcinoma cells transfected with DAB2 showed a reduced growth rate and ability to form tumors in nude mice. Loss of DAB2 expression is not correlated with tumor grade, suggesting that loss of DAB2 expression is an early event in ovarian malignancies and DAB2 behaves as a tumor suppressor.
    Entity name
    Prostate cancer
    Note
    DAB2 is a potent growth inhibitor for prostate cancer cells by suppressing several protein kinase pathways. The PRD of DAB2 is the key functional domain responsible for this activity. It was shown that in prostate cancer cells without endogenous DAB2 expression, a functional motif derived from the PRD of DAB2 conjugated with a delivery system is a potent growth inhibitor.
    Entity name
    Breast cancer
    Note
    DAB2 sensitizes breast cancer cells to cell death upon the loss of cell-matrix attachment by targeting the oncogenic activity of ILK.
    Entity name
    Various cancer
    Note
    Urothelial carcinoma of the bladder, esophageal squamous carcinoma, metastatic pancreatic cancer, colorectal cancer, gestational choriocarcinoma.
    Disease
    DAB2 expression is down-regulated.
    Entity name
    Malignant peripheral nerve sheath tumor, invasive cervical carcinoma
    Note
    Comparative genomic hybridization (CGH) revealed frequent gains of DAB2.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    86609691996Sequence, genomic structure, and chromosomal assignment of human DOC-2.Albertsen HM et al
    103403821999Disabled-2 inactivation is an early step in ovarian tumorigenicity.Fazili Z et al
    113597722001Disabled-2 exerts its tumor suppressor activity by uncoupling c-Fos expression and MAP kinase activation.He J et al
    128817092003Cell cycle-dependent phosphorylation of Disabled-2 by cdc2.He J et al
    160046142005Microarray comparative genomic hybridization detection of chromosomal imbalances in uterine cervix carcinoma.Hidalgo A et al
    113872122001The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway.Hocevar BA et al
    152803742004Disabled-2 is a negative regulator of integrin alpha(IIb)beta(3)-mediated fibrinogen adhesion and cell signaling.Huang CL et al
    179220362008The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin.Jiang Y et al
    176711222007Decreased DOC-2/DAB2 expression in urothelial carcinoma of the bladder.Karam JA et al
    122349312002Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor.Mishra SK et al
    96205551998DOC-2, a candidate tumor suppressor gene in human epithelial ovarian cancer.Mok SC et al
    112473022001Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2.Morris SM et al
    163918452006Chromosomal imbalances in malignant peripheral nerve sheath tumor detected by metaphase and microarray comparative genomic hybridization.Nakagawa Y et al
    185824652008Morphogenesis of human endothelial cells is inhibited by DAB2 via Src.Orlandini M et al
    157347302005Disabled-2 (Dab2) is required for transforming growth factor beta-induced epithelial to mesenchymal transition (EMT).Prunier C et al
    118234142002Disabled-2 is transcriptionally regulated by ICSBP and augments macrophage spreading and adhesion.Rosenbauer F et al
    111617892000Structure, sequence, and promoter analysis of human disabled-2 gene (DAB2).Sheng Z et al
    115770912001Disabled-2 mediates c-Fos suppression and the cell growth regulatory activity of retinoic acid in embryonic carcinoma cells.Smith ER et al
    171870612007Myosin VI targeting to clathrin-coated structures and dimerization is mediated by binding to Disabled-2 and PtdIns(4,5)P2.Spudich G et al
    105422281999The role of DOC-2/DAB2 protein phosphorylation in the inhibition of AP-1 activity. An underlying mechanism of its tumor-suppressive function in prostate cancer.Tseng CP et al
    116879762001DOC-2/hDab-2 inhibits ILK activity and induces anoikis in breast cancer cells through an Akt-independent pathway.Wang SC et al
    77754791995Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product.Xu XX et al
    173393202007Disabled-2 is an epithelial surface positioning gene.Yang DH et al
    191912182009C-Fos elimination compensates for disabled-2 requirement in mouse extraembryonic endoderm development.Yang DH et al
    169827332006Inhibition of mitogen-elicited signal transduction and growth in prostate cancer with a small peptide derived from the functional domain of DOC-2/DAB2 delivered by a unique vehicle.Zhou J et al
    113715632001The inhibitory role of DOC-2/DAB2 in growth factor receptor-mediated signal cascade. DOC-2/DAB2-mediated inhibition of ERK phosphorylation via binding to Grb2.Zhou J et al
    124736512003Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal prostatic epithelium and cancer.Zhou J et al
    162670152005The role of DOC-2/DAB2 in modulating androgen receptor-mediated cell growth via the nongenomic c-Src-mediated pathway in normal prostatic epithelium and cancer.Zhoul J et al

    Other Information

    Locus ID:

    NCBI: 1601
    MIM: 601236
    HGNC: 2662
    Ensembl: ENSG00000153071

    Variants:

    dbSNP: 1601
    ClinVar: 1601
    TCGA: ENSG00000153071
    COSMIC: DAB2

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000153071ENST00000320816P98082
    ENSG00000153071ENST00000320816A0A024R036
    ENSG00000153071ENST00000339788P98082
    ENSG00000153071ENST00000503513D6REB1
    ENSG00000153071ENST00000507539D6RFF7
    ENSG00000153071ENST00000509337P98082
    ENSG00000153071ENST00000511792D6RIA5
    ENSG00000153071ENST00000515700D6RGZ1
    ENSG00000153071ENST00000545653P98082

    Expression (GTEx)

    0
    50
    100
    150
    200

    Pathways

    PathwaySourceExternal ID
    EndocytosisKEGGko04144
    EndocytosisKEGGhsa04144
    Vesicle-mediated transportREACTOMER-HSA-5653656
    Membrane TraffickingREACTOMER-HSA-199991
    Gap junction trafficking and regulationREACTOMER-HSA-157858
    Gap junction traffickingREACTOMER-HSA-190828
    Gap junction degradationREACTOMER-HSA-190873
    Formation of annular gap junctionsREACTOMER-HSA-196025
    Clathrin-mediated endocytosisREACTOMER-HSA-8856828
    Cargo recognition for clathrin-mediated endocytosisREACTOMER-HSA-8856825

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    203831462010New loci associated with kidney function and chronic kidney disease.337
    168707012006A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors.71
    169849702006The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH.71
    192047262009Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.63
    203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
    118127852002The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2.55
    217253662012Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2.47
    158945422005Disabled-2 (Dab2) mediates transforming growth factor beta (TGFbeta)-stimulated fibronectin synthesis through TGFbeta-activated kinase 1 and activation of the JNK pathway.46
    195814122009Quantitative proteomics identifies a Dab2/integrin module regulating cell migration.44
    205924732010Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter.42

    Citation

    Maurizio Orlandini

    DAB2 (disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila))

    Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

    Online version: http://atlasgeneticsoncology.org/gene/40258/dab2