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Protein

Disabled homolog 2

Gene

Dab2

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Adapter protein that functions as clathrin-associated sorting protein (CLASP) required for clathrin-mediated endocytosis of selected cargo proteins. Can bind and assemble clathrin, and binds simultaneously to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and cargos containg non-phosphorylated NPXY internalization motifs, such as the LDL receptor, to recruit them to clathrin-coated pits. Can function in clathrin-mediated endocytosis independently of the AP-2 complex. Involved in endocytosis of integrin beta-1; this function seems to redundant with the AP-2 complex and seems to require DAB2 binding to endocytosis accessory EH domain-containing proteins such as EPS15, EPS15L1 and ITSN1. Involved in endocytosis of cystic fibrosis transmembrane conductance regulator/CFTR. Involved in endocytosis of megalin/LRP2 lipoprotein receptor during embryonal development. Required for recycling of the TGF-beta receptor. Involved in CFTR trafficking to the late endosome. Involved in several receptor-mediated signaling pathways. Involved in TGF-beta receptor signaling and facilitates phosphorylation of the signal transducer SMAD2. Mediates TFG-beta-stimulated JNK activation. May inhibit the canoniocal Wnt/beta-catenin signaling pathway by stabilizing the beta-catenin destruction complex through a competing association with axin preventing its dephosphorylation through protein phosphatase 1 (PP1). Sequesters LRP6 towards clathrin-mediated endocytosis, leading to inhibition of Wnt/beta-catenin signaling. May activate non-canonical Wnt signaling. In cell surface growth factor/Ras signaling pathways proposed to inhibit ERK activation by interrupting the binding of GRB2 to SOS1 and to inhibit SRC by preventing its activating phosphorylation at 'Tyr-419'. Proposed to be involved in modulation of androgen receptor (AR) signaling mediated by SRC activation; seems to compete with AR for interaction with SRC. Plays a role in the CSF-1 signal transduction pathway. Plays a role in cellular differentiation. Involved in cell positioning and formation of visceral endoderm (VE) during embryogenesis and proposed to be required in the VE to respond to Nodal signaling coming from the epiblast. Required for the epithelial to mesenchymal transition, a process necessary for proper embryonic development. May be involved in myeloid cell differentiation and can induce macrophage adhesion and spreading. May act as a tumor suppressor.2 Publications

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • cellular response to epidermal growth factor stimulus Source: UniProtKB
  • cellular response to transforming growth factor beta stimulus Source: RGD
  • clathrin coat assembly Source: RGD
  • endocytosis Source: UniProtKB-KW
  • negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
  • negative regulation of cell growth Source: RGD
  • negative regulation of epithelial cell proliferation Source: RGD
  • negative regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • negative regulation of neuron projection development Source: RGD
  • positive regulation of aldosterone biosynthetic process Source: RGD
  • positive regulation of aldosterone secretion Source: RGD
  • positive regulation of endocytosis Source: RGD
  • positive regulation of substrate adhesion-dependent cell spreading Source: RGD
  • protein transport Source: UniProtKB-KW
  • regulation of Rho-dependent protein serine/threonine kinase activity Source: RGD
  • response to salt Source: RGD
  • response to steroid hormone Source: RGD
  • Wnt signaling pathway Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Apoptosis, Differentiation, Endocytosis, Protein transport, Transport, Wnt signaling pathway

Names & Taxonomyi

Protein namesi
Recommended name:
Disabled homolog 2
Alternative name(s):
Adaptor molecule disabled-2
C9
Differentially expressed in ovarian carcinoma 2
Short name:
DOC-2
Mitogen-responsive phosphoprotein
Gene namesi
Name:Dab2
Synonyms:Doc2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi621007. Dab2.

Subcellular locationi

GO - Cellular componenti

  • clathrin-coated vesicle membrane Source: RGD
  • coated pit Source: UniProtKB-SubCell
  • perinuclear region of cytoplasm Source: RGD
  • plasma membrane Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Coated pit, Cytoplasm, Cytoplasmic vesicle, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi393 – 3931S → A: Reduces phosphorylation, reduces mitotic membrane displacement; when associated with A-394 and A-401. 1 Publication
Mutagenesisi394 – 3941S → A: Reduces phosphorylation, reduces mitotic membrane displacement; when associated with A-393 and A-401. 1 Publication
Mutagenesisi401 – 4011S → A: Reduces phosphorylation, reduces mitotic membrane displacement; when associated with A-393 and A-394. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy similarity
Chaini2 – 768767Disabled homolog 2PRO_0000079772Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserineBy similarity
Modified residuei2 – 21PhosphoserineCombined sources
Modified residuei170 – 1701PhosphotyrosineBy similarity
Modified residuei193 – 1931PhosphoserineCombined sources
Modified residuei326 – 3261Phosphoserine; in mitosis1 Publication
Modified residuei328 – 3281Phosphoserine; in mitosis1 Publication
Modified residuei401 – 4011PhosphoserineCombined sources
Modified residuei673 – 6731PhosphothreonineBy similarity
Modified residuei675 – 6751PhosphoserineBy similarity
Modified residuei729 – 7291PhosphoserineCombined sources
Modified residuei761 – 7611PhosphoserineBy similarity

Post-translational modificationi

Phosphorylated. Phosphorylation during mitosis is leading to membrane displacement. There is some ambiguity for the mitotic phosphosite Ser-326/328.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiO88797.
PRIDEiO88797.

PTM databases

iPTMnetiO88797.
PhosphoSiteiO88797.

Expressioni

Tissue specificityi

Prostate.1 Publication

Interactioni

Subunit structurei

Can interact (via PID domain) with LDLR, APP, APLP1 and APLP2, and weakly with INPP5D (via NPXY motifs); the interaction is impaired by tyrosine phosphorylation of the respective NPXY motifs. Can weakly interact (via PID domain) with LRP1 (via NPXY motif); the interaction is enhanced by tyrosine phosphorylation of the NPXY motif. Interacts with LRP2 (via NPXY motif); the interaction is not affected by tyrosine phosphorylation of the NPXY motif. Interacts with clathrin; in vitro can assemble clathrin triskelia into polyhedral coats. Interacts with AP2A2, ITGB1, ITGB3, ITGB5, PIAS2, DAB2IP, NOSTRIN, FCHO1, DVL3, EPS15, ITSN1 and EPS15L1. Interacts with SH3KBP1 (via SH3 domains). Interacts with GRB2; competes with SOS1 for binding to GRB2 and the interaction is enhanced by EGF and NT-3 stimulation. Interacts with MAP3K7; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation. Interacts with AXIN1 and PPP1CA; the interactions are mutually exclusive. Interacts with the globular tail of MYO6. Interacts (via DPF motifs) with FCHO2; the interaction is direct and required for DAB2-mediated LDLR endocytosis. Interacts with LRP6; the interaction involves LRP6 phosphorylation by CK2 and sequesters LRP6 towards clathrin-mediated endocytosis. Associates with the TGF-beta receptor complex (Probable). Interacts with SMAD2 and SMAD3; the interactions are enhanced upon TGF-beta stimulation. Interacts with GRB2; the interaction is enhanced by EGF and NT-3 stimulation. Interacts with SRC; the interaction is enhanced by EGF stimulation. Interacts with GRB2; the interaction is enhanced by EGF and NT-3 stimulation. Interacts (via NPXY motif) with DAB2 (via PID domain).Curated3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Lrp2P981582EBI-6109302,EBI-6306650

Protein-protein interaction databases

BioGridi249412. 1 interaction.
DIPiDIP-60713N.
IntActiO88797. 3 interactions.
STRINGi10116.ENSRNOP00000043878.

Structurei

Secondary structure

1
768
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi680 – 68910Combined sources
Helixi699 – 71113Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3H8DX-ray2.20E/F/G/H675-713[»]
ProteinModelPortaliO88797.
SMRiO88797. Positions 33-172.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO88797.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini45 – 196152PIDPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni230 – 447218Required for localization to clathrin-coated pitsBy similarityAdd
BLAST
Regioni601 – 731131Sufficient for interaction with GRB2By similarityAdd
BLAST
Regioni619 – 6279Required for interaction with CSK
Regioni649 – 768120Required for interaction with MYO6By similarityAdd
BLAST
Regioni663 – 6719Required for interaction with GRB2 and CSK
Regioni708 – 72417Sufficient for interaction with SH3KBP1 SH3 domainBy similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi293 – 2953DPF 1
Motifi298 – 3003DPF 2

Domaini

The PID domain binds to predominantly non-phosphorylated NPXY internalization motifs present in members of the LDLR and APP family; it also mediates simultaneous binding to phosphatidylinositol 4,5-bisphosphate.By similarity
The Asn-Pro-Phe (NPF) motifs, which are found in proteins involved in the endocytic pathway, mediate the interaction with the EH domain of EPS15, EPS15R and ITSN1.By similarity

Sequence similaritiesi

Contains 1 PID domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG3535. Eukaryota.
ENOG410XZ1H. LUCA.
HOVERGENiHBG018945.
InParanoidiO88797.
KOiK12475.
PhylomeDBiO88797.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
InterProiIPR011993. PH_dom-like.
IPR006020. PTB/PI_dom.
[Graphical view]
PfamiPF00640. PID. 1 hit.
[Graphical view]
SMARTiSM00462. PTB. 1 hit.
[Graphical view]
SUPFAMiSSF50729. SSF50729. 1 hit.
PROSITEiPS01179. PID. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform p82 (identifier: O88797-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSNEVETSTT NGQPDQQAAP KAPSKKEKKK GSEKTDEYLL ARFKGDGVKY
60 70 80 90 100
KAKLIGIDDV PDARGDKMSQ DSMMKLKGMA AAGRSQGQHK QRIWVNISLS
110 120 130 140 150
GIKIIDEKTG VIEHEHPVNK ISFIARDVTD NRAFGYVCGG EGQHQFFAIK
160 170 180 190 200
TGQQAEPLVV DLKDLFQVIY NVKKKEEEKK KVEEANKAEE NGSEALMTLD
210 220 230 240 250
DQANKLKLGV DQMDLFGDMS TPPDLNNPTE SRDILLVDLN SEIDTNQNSL
260 270 280 290 300
RENPFLTNGV TSCSLPRPKP QASFLPESAF SANLNFFPTP NPDPFRDDPF
310 320 330 340 350
AQPDQSAPSS FHSLTSADQK KANPGSLSTP QSKGPLNGDT DYFGQQFDQI
360 370 380 390 400
SNRTGKQEAQ GGPWPYPSSQ TQQAVRTQNG VSEKEQNGFH IKSSPNPFVG
410 420 430 440 450
SPPKGLSVPN GVKQDLESSV QSSAHDSIAI IPPPQSTKPG RGRRTAKSSA
460 470 480 490 500
NDLLASDIFA SEPPGQMSPT GQPAVPQANF MDLFKTSAPA PMGSGPLVGL
510 520 530 540 550
GTVPVTPPQA GPWTPVVFTP STTVVPGAII SGQPSGFGQP LVFGTTPAVQ
560 570 580 590 600
VWNQPSSFAT AASPPPPAVW CPTTSVAPNT WSSTSPLGNP FQSSNIFPPS
610 620 630 640 650
TISTQSFPQP MMSSVLVTPP QPPPRNGPLK DTLSDAFTGL DPLGDKEVKE
660 670 680 690 700
VKEMFKDFQL RQPPLVPSRK GETPSSGTSS AFSSYFNNKV GIPQEHVDHD
710 720 730 740 750
DFDANQLLNK INEPPKPAPR QGVLSGTKSA DNSLENPFSK GFSSTNPSVV
760
SQPASSDAHR SPFGNPFA
Length:768
Mass (Da):82,377
Last modified:November 1, 1998 - v1
Checksum:i930FB25248ADAC6E
GO
Isoform p59 (identifier: O88797-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     230-447: Missing.

Show »
Length:550
Mass (Da):58,880
Checksum:iE5F16C758901BE10
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti3 – 42NE → TN in AAC03360 (Ref. 3) Curated
Sequence conflicti186 – 1861N → K in AAC03361 (Ref. 3) Curated
Sequence conflicti675 – 6751S → P in AAC03362 (Ref. 3) Curated
Sequence conflicti764 – 7685GNPFA → WKSFC in AAC03363 (Ref. 3) Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei230 – 447218Missing in isoform p59. 1 PublicationVSP_004184Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U95177 mRNA. Translation: AAC33405.1.
U95178 mRNA. Translation: AAC33406.1.
BC097314 mRNA. Translation: AAH97314.1.
AF045657 mRNA. Translation: AAC03360.1.
AF045658 mRNA. Translation: AAC03361.1.
AF045659 mRNA. Translation: AAC03362.1.
AF045660 mRNA. Translation: AAC03363.1.
RefSeqiNP_077073.1. NM_024159.1. [O88797-1]
UniGeneiRn.161784.

Genome annotation databases

GeneIDi79128.
KEGGirno:79128.
UCSCiRGD:621007. rat. [O88797-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U95177 mRNA. Translation: AAC33405.1.
U95178 mRNA. Translation: AAC33406.1.
BC097314 mRNA. Translation: AAH97314.1.
AF045657 mRNA. Translation: AAC03360.1.
AF045658 mRNA. Translation: AAC03361.1.
AF045659 mRNA. Translation: AAC03362.1.
AF045660 mRNA. Translation: AAC03363.1.
RefSeqiNP_077073.1. NM_024159.1. [O88797-1]
UniGeneiRn.161784.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3H8DX-ray2.20E/F/G/H675-713[»]
ProteinModelPortaliO88797.
SMRiO88797. Positions 33-172.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249412. 1 interaction.
DIPiDIP-60713N.
IntActiO88797. 3 interactions.
STRINGi10116.ENSRNOP00000043878.

PTM databases

iPTMnetiO88797.
PhosphoSiteiO88797.

Proteomic databases

PaxDbiO88797.
PRIDEiO88797.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi79128.
KEGGirno:79128.
UCSCiRGD:621007. rat. [O88797-1]

Organism-specific databases

CTDi1601.
RGDi621007. Dab2.

Phylogenomic databases

eggNOGiKOG3535. Eukaryota.
ENOG410XZ1H. LUCA.
HOVERGENiHBG018945.
InParanoidiO88797.
KOiK12475.
PhylomeDBiO88797.

Miscellaneous databases

EvolutionaryTraceiO88797.
PROiO88797.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
InterProiIPR011993. PH_dom-like.
IPR006020. PTB/PI_dom.
[Graphical view]
PfamiPF00640. PID. 1 hit.
[Graphical view]
SMARTiSM00462. PTB. 1 hit.
[Graphical view]
SUPFAMiSSF50729. SSF50729. 1 hit.
PROSITEiPS01179. PID. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Regulation of rat DOC-2 gene during castration-induced rat ventral prostate degeneration and its growth inhibitory function in human prostatic carcinoma cells."
    Tseng C.-P., Ely B.D., Li Y., Pong R.-C., Hsieh J.-T.
    Endocrinology 139:3542-3553(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS P59 AND P82), TISSUE SPECIFICITY.
    Strain: Sprague-Dawley.
    Tissue: Prostate.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P82).
    Tissue: Placenta.
  3. Lau K.M., Mok S.C., Ho S.M.
    Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 2-47; 117-189; 634-687 AND 753-768.
    Tissue: Kidney and Prostate.
  4. "The 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."
    Wang Z., Tseng C.-P., Pong R.-C., Chen H., McConnell J.D., Navone N., Hsieh J.-T.
    J. Biol. Chem. 277:12622-12631(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH DAB2IP.
  5. "Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal prostatic epithelium and cancer."
    Zhou J., Scholes J., Hsieh J.T.
    J. Biol. Chem. 278:6936-6941(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH GRB2 AND SRC.
  6. "Dab2 regulates clathrin assembly and cell spreading."
    Chetrit D., Ziv N., Ehrlich M.
    Biochem. J. 418:701-715(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  7. "Negative regulation of the endocytic adaptor disabled-2 (Dab2) in mitosis."
    Chetrit D., Barzilay L., Horn G., Bielik T., Smorodinsky N.I., Ehrlich M.
    J. Biol. Chem. 286:5392-5403(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-326; SER-328 AND SER-401, MUTAGENESIS OF SER-393; SER-394 AND SER-401.
  8. "Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues."
    Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., Olsen J.V.
    Nat. Commun. 3:876-876(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2; SER-193; SER-401 AND SER-729, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  9. "Myosin VI undergoes cargo-mediated dimerization."
    Yu C., Feng W., Wei Z., Miyanoiri Y., Wen W., Zhao Y., Zhang M.
    Cell 138:537-548(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 675-713 IN COMPLEX WITH MYO6.

Entry informationi

Entry nameiDAB2_RAT
AccessioniPrimary (citable) accession number: O88797
Secondary accession number(s): O55048
, O55049, O55050, O55051, O88798, Q4QRA2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 11, 2002
Last sequence update: November 1, 1998
Last modified: July 6, 2016
This is version 117 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.