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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 containing 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

Keywordsi

Molecular functionDevelopmental protein
Biological processApoptosis, 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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi621007. Dab2.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Coated pit, Cytoplasm, Cytoplasmic vesicle, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi393S → A: Reduces phosphorylation, reduces mitotic membrane displacement; when associated with A-394 and A-401. 1 Publication1
Mutagenesisi394S → A: Reduces phosphorylation, reduces mitotic membrane displacement; when associated with A-393 and A-401. 1 Publication1
Mutagenesisi401S → A: Reduces phosphorylation, reduces mitotic membrane displacement; when associated with A-393 and A-394. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000797722 – 768Disabled homolog 2Add BLAST767

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei2PhosphoserineCombined sources1
Modified residuei170PhosphotyrosineBy similarity1
Modified residuei193PhosphoserineCombined sources1
Modified residuei326Phosphoserine; in mitosis1 Publication1
Modified residuei328Phosphoserine; in mitosis1 Publication1
Modified residuei401PhosphoserineCombined sources1
Modified residuei673PhosphothreonineBy similarity1
Modified residuei675PhosphoserineBy similarity1
Modified residuei729PhosphoserineCombined sources1
Modified residuei761PhosphoserineBy similarity1

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.
PhosphoSitePlusiO88797.

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 interactor.
DIPiDIP-60713N.
IntActiO88797. 3 interactors.
STRINGi10116.ENSRNOP00000043878.

Structurei

Secondary structure

1768
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi680 – 689Combined sources10
Helixi699 – 711Combined sources13

3D structure databases

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

Miscellaneous databases

EvolutionaryTraceiO88797.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini45 – 196PIDPROSITE-ProRule annotationAdd BLAST152

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni230 – 447Required for localization to clathrin-coated pitsBy similarityAdd BLAST218
Regioni601 – 731Sufficient for interaction with GRB2By similarityAdd BLAST131
Regioni619 – 627Required for interaction with CSK9
Regioni649 – 768Required for interaction with MYO6By similarityAdd BLAST120
Regioni663 – 671Required for interaction with GRB2 and CSK1 Publication9
Regioni708 – 724Sufficient for interaction with SH3KBP1 SH3 domainBy similarityAdd BLAST17

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi293 – 295DPF 13
Motifi298 – 300DPF 23

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

Phylogenomic databases

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

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
InterProiView protein in InterPro
IPR011993. PH_dom-like.
IPR006020. PTB/PI_dom.
PfamiView protein in Pfam
PF00640. PID. 1 hit.
SMARTiView protein in SMART
SM00462. PTB. 1 hit.
SUPFAMiSSF50729. SSF50729. 1 hit.
PROSITEiView protein in PROSITE
PS01179. PID. 1 hit.

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)DescriptionActionsGraphical viewLength
Sequence conflicti3 – 4NE → TN in AAC03360 (Ref. 3) Curated2
Sequence conflicti186N → K in AAC03361 (Ref. 3) Curated1
Sequence conflicti675S → P in AAC03362 (Ref. 3) Curated1
Sequence conflicti764 – 768GNPFA → WKSFC in AAC03363 (Ref. 3) Curated5

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004184230 – 447Missing in isoform p59. 1 PublicationAdd BLAST218

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

Similar proteinsi

Entry informationi

Entry nameiDAB2_RAT
AccessioniPrimary (citable) accession number: O88797
Secondary accession number(s): O55048
, O55049, O55050, O55051, O88798, Q4QRA2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 11, 2002
Last sequence update: November 1, 1998
Last modified: August 30, 2017
This is version 124 of the entry and version 1 of the sequence. See 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