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Protein

Disabled homolog 2-interacting protein

Gene

Dab2ip

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

Functioni

Functions as a scaffold protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Involved in several processes such as innate immune response, inflammation and cell growth inhibition, apoptosis, cell survival, angiogenesis, cell migration and maturation. Plays also a role in cell cycle checkpoint control; reduces G1 phase cyclin levels resulting in G0/G1 cell cycle arrest. Mediates signal transduction by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF), interferon (IFN) or lipopolysaccharide (LPS). Modulates the balance between phosphatidylinositol 3-kinase (PI3K)-AKT-mediated cell survival and apoptosis stimulated kinase (MAP3K5)-JNK signaling pathways; sequesters both AKT1 and MAP3K5 and counterbalances the activity of each kinase by modulating their phosphorylation status in response to proinflammatory stimuli. Acts as a regulator of the endoplasmic reticulum (ER) unfolded protein response (UPR) pathway; specifically involved in transduction of the ER stress-response to the JNK cascade through ERN1. Mediates TNF-alpha-induced apoptosis activation by facilitating dissociation of inhibitor 14-3-3 from MAP3K5; recruits the PP2A phosphatase complex which dephosphorylates MAP3K5 on 'Ser-966', leading to the dissociation of 13-3-3 proteins and activation of the MAP3K5-JNK signaling pathway in endothelial cells. Acts a negative regulator in the IFN-gamma-mediated JAK-STAT signaling cascade by inhibiting smooth muscle cell (VSMCs) proliferation and intimal expansion, and thus, prevents graft arteriosclerosis (GA). Acts as a GTPase-activating protein (GAP) for the ADP ribosylation factor 6 (ARF6). Promotes hydrolysis of the ARF6-bound GTP and thus, negatively regulates phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent TLR4-TIRAP-MyD88 and NF-kappa-B signaling pathways in endothelial cells in response to lipopolysaccharides (LPS). Binds specifically to phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 3-phosphate (PtdIns3P). In response to vascular endothelial growth factor (VEGFA), acts as a negative regulator of the VEGFR2-PI3K-mediated angiogenic signaling pathway by inhibiting endothelial cell migration and tube formation. In the developing brain, promotes both the transition from the multipolar to the bipolar stage and the radial migration of cortical neurons from the ventricular zone toward the superficial layer of the neocortex in a glial-dependent locomotion process. Probable downstream effector of the Reelin signaling pathway; promotes Purkinje cell (PC) dendrites development and formation of cerebellar synapses. Functions also as a tumor suppressor protein in prostate cancer progression; prevents cell proliferation and epithelial-to-mesenchymal transition (EMT) through activation of the glycogen synthase kinase-3 beta (GSK3B)-induced beta-catenin and inhibition of PI3K-AKT and Ras-MAPK survival downstream signaling cascades, respectively (By similarity). Mediates TNF/TRAF2-induced MAP3K5-JNK activation, while it inhibits CHUK-NF-kappa-B signaling. Functions as a Ras GTPase-activating protein. May act as a tumor suppressor gene.By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, GTPase activation

Keywords - Biological processi

Angiogenesis, Apoptosis, Cell cycle, Growth regulation, Stress response, Unfolded protein response

Enzyme and pathway databases

ReactomeiR-RNO-5658442. Regulation of RAS by GAPs.
R-RNO-8849471. PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.

Names & Taxonomyi

Protein namesi
Recommended name:
Disabled homolog 2-interacting protein
Short name:
DAB2-interacting protein
Alternative name(s):
ASK-interacting protein 1
Short name:
AIP-1
DIP1/2
DOC-2/DAB2 interactive protein
Gene namesi
Name:Dab2ip
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 3

Organism-specific databases

RGDi621686. Dab2ip.

Subcellular locationi

  • Cytoplasm By similarity
  • Cell membrane By similarity; Peripheral membrane protein By similarity
  • Membrane By similarity
  • Cell projectiondendrite By similarity

  • Note: Localized in soma and dendrites of Purkinje cells as well as in scattered cell bodies in the molecular layer of the cerebellum. Colocalizes with TIRAP at the plasma membrane. Colocalizes with ARF6 at the plasma membrane and endocytic vesicles. Translocates from the plasma membrane to the cytoplasm in response to TNF-alpha. Phosphatidylinositol 4-phosphate (PtdIns4P) binding is essential for plasma membrane localization (By similarity).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi220 – 2201R → L: Loss of GAP activity. 1 Publication

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 996996Disabled homolog 2-interacting proteinPRO_0000252409Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei535 – 5351Phosphoserine; by MAP3K5 and RIPK1By similarity
Modified residuei554 – 5541PhosphoserineCombined sources
Modified residuei785 – 7851PhosphoserineBy similarity
Modified residuei802 – 8021PhosphoserineBy similarity

Post-translational modificationi

In response to TNF-alpha-induction, phosphorylated at Ser-535; phosphorylation leads to a conformational change, and thus, increases its association with 14-3-3 proteins, MAP3K5, RIPK1 and TRAF2 in endothelial cells; also stimulates regulatory p85 subunit sequestring and PI3K-p85 complex activity inhibition.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ6P730.
PRIDEiQ6P730.

PTM databases

iPTMnetiQ6P730.
PhosphoSiteiQ6P730.

Expressioni

Tissue specificityi

Expressed in brain, lung, thymus, bladder and skeletal muscle. Up-regulatedd during prostate degeneration.1 Publication

Gene expression databases

GenevisibleiQ6P730. RN.

Interactioni

Subunit structurei

On plasma membrane, exists in an inactive form complexed with TNFR1; in response to TNF-alpha, dissociates from TNFR1 complex, tranlocates to cytoplasm and forms part of an intracellular signaling complex comprising TRADD, RALBP1, TRAF2 and MAP3K5. Interacts (via NPXY motif) with DAB2 (via PID domain). Interacts (via PH domain) with ERN1. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF-alpha; this complex formation promotes MAP3K5-JNK activation and subsequent apoptosis. Interacts (via N-terminal domain) with JAK2; the interaction occurs in a IFNG/IFN-gamma-dependent manner and inhibits JAK2 autophosphorylation activity. Interacts (via C2 domain) with GSK3B; the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA. Interacts (via proline-rich motif) with a regulatory p85 subunit (via SH3 domain) of the PI3K complex; the interaction inhibits the PI3K-AKT complex activity in a TNF-alpha-dependent manner in prostate cancer (PCa) cells. Interacts with AKT1; the interaction is increased in a TNF-alpha-induced manner. Interacts (via C2 domain and active form preferentially) with KDR/VEGFR2 (tyrosine-phosphorylated active form preferentially); the interaction occurs at the late phase of VEGFA response and inhibits KDR/VEGFR2 activity. Interacts (via N-terminus C2 domain) with MAP3K5 ('Ser-966' dephosphorylated form preferentially); the interaction occurs in a TNF-alpha-induced manner. Interacts (via Ras-GAP domain) with the catalytic subunit of protein phosphatase PP2A; the interaction occurs in resting endothelial cells, is further enhanced by TNF-alpha stimulation and is required to bridge PP2A to MAP3K5. Interacts (via C-terminus PER domain) with TRAF2 (via zinc fingers); the interaction occurs in a TNF-alpha-dependent manner. Interacts with 14-3-3 proteins; the interaction occurs in a TNF-alpha-dependent manner. Interacts (via Ras-GAP domain) with RIPK1 (via kinase domain); the interaction occurs in a TNF-alpha-dependent manner (By similarity). Interacts with DAB1 and DAB2.By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000056740.

Structurei

3D structure databases

ProteinModelPortaliQ6P730.
SMRiQ6P730. Positions 113-463.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini7 – 10296C2Add
BLAST
Domaini178 – 370193Ras-GAPPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni453 – 750298Necessary for interaction with AKT1By similarityAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili832 – 966135Sequence analysisAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi674 – 6774Poly-Ala
Compositional biasi710 – 75546Pro-richAdd
BLAST

Domaini

Exists in a closed inactive form by an intramolecular interaction between the N- and the C-terminal domains. The proline-rich motif is critical both for PI3K-AKT activity inhibition and MAP3K5 activation. The PH and C2 domains are necessary for the binding to phosphatidylinositol phosphate. The Ras-GAP domain is necessary for its tumor-suppressive function. The C2 and Ras-GAP domains constitutively bind to MAP3K5 and facilitate the release of 14-3-3 proteins from MAP3K5. The PH and Ras-GAP domains, but not the NPXY motif, are crucial for its cell membrane localization and neuronal migration function. The PH domain is necessary but not sufficient to activate the JNK signaling pathway through ERN1 (By similarity).By similarity

Sequence similaritiesi

Contains 1 C2 domain.Curated
Contains 1 Ras-GAP domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG3508. Eukaryota.
ENOG410XPU1. LUCA.
GeneTreeiENSGT00760000119092.
HOGENOMiHOG000231979.
HOVERGENiHBG006492.
InParanoidiQ6P730.
KOiK19901.
OrthoDBiEOG74XS5P.

Family and domain databases

Gene3Di1.10.506.10. 1 hit.
2.60.40.150. 1 hit.
InterProiIPR000008. C2_dom.
IPR030403. DAB2IP.
IPR021887. DUF3498.
IPR023152. RasGAP_CS.
IPR001936. RasGAP_dom.
IPR008936. Rho_GTPase_activation_prot.
[Graphical view]
PANTHERiPTHR10194:SF26. PTHR10194:SF26. 1 hit.
PfamiPF00168. C2. 1 hit.
PF12004. DUF3498. 1 hit.
PF00616. RasGAP. 2 hits.
[Graphical view]
SMARTiSM00239. C2. 1 hit.
SM00323. RasGAP. 1 hit.
[Graphical view]
SUPFAMiSSF48350. SSF48350. 1 hit.
SSF49562. SSF49562. 1 hit.
PROSITEiPS00509. RAS_GTPASE_ACTIV_1. 1 hit.
PS50018. RAS_GTPASE_ACTIV_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q6P730-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MENLRRAVHP NKDNSRRVEH ILKLWVIEAK DLPAKKKYLC ELCLDDVLYA
60 70 80 90 100
RTTGKLKTDN VFWGEHFEFH NLPPLRTVTV HLYRETDKKK KKERNSYLGL
110 120 130 140 150
VSLPAASVAG RQFVEKWYPV VTPNPKGGKG PGPMIRIKAR YQTITILPME
160 170 180 190 200
MYKEFAEHIT NHYLGLCAAL EPILSAKTKE EMASALVHIL QSTGKVKDFL
210 220 230 240 250
TDLMMSEVDR CGDNEHLIFR ENTLATKAIE EYLKLVGQKY LQDALGEFIK
260 270 280 290 300
ALYESDENCE VDPSKCSAAD LPEHQGNLKM CCELAFCKII NSYCVFPREL
310 320 330 340 350
KEVFASWRQE CSSRGRPDIS ERLISASLFL RFLCPAIMSP SLFNLLQEYP
360 370 380 390 400
DDRTARTLTL IAKVTQNLAN FAKFGSKEEY MSFMNQFLEH EWTNMQRFLL
410 420 430 440 450
EISNPETLSN TAGFEGYIDL GRELSSLHSL LWEAVSQLDQ SIVSKLGPLP
460 470 480 490 500
RILRDVHTAL STPGSGQLPG TNDLASTPGS GSSSVSAGLQ KMVIENDLSG
510 520 530 540 550
LIDFTRLPSP TPENKDLFFV TRSSGVQPSP ARSSSYSEAN EPDLQMANGS
560 570 580 590 600
KSLSMVDLQD ARTLDGEAGS PVGPEALPAD GQVPATQLVA GWPARAAPVS
610 620 630 640 650
LAGLATVRRA VPTPTTPGTS EGAPGRPQLL APLSFQNPVY QMAAGLPLSP
660 670 680 690 700
RGLGDSGSEG HSSLSSHSNS EELAAAAKLG SFSTAAEELA RRPGELARRQ
710 720 730 740 750
MSLTEKGGQP TVPRQNSAGP QRRIDQPPPP PPPPPPAPRG RTPPTMLSTL
760 770 780 790 800
QYPRPSSGTL ASASPDWAGP GTRLRQQSSS SKGDSPELKP RALHKQGPSP
810 820 830 840 850
VSPNALDRTA AWLLTMNAQL LEDEGLGPDP PHRDRLRSKE ELSQAEKDLA
860 870 880 890 900
VLQDKLRIST KKLEEYETLF KCQEETTQKL VLEYQARLEE GEERLRRQQE
910 920 930 940 950
DKDVQMKGII SRLMSVEEEL KKDHAEMQAA VDSKQKIIDA QEKRIASLDA
960 970 980 990
ANARLMSALT QLKERYSMRA RNGVSPTNPT KLQITENGEF RNSSNC
Length:996
Mass (Da):110,005
Last modified:July 5, 2004 - v1
Checksum:iCA6B43D3129F4D6E
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti228 – 2281A → G in AAK93947 (PubMed:11812785).Curated
Sequence conflicti238 – 2381Q → H in AAK93947 (PubMed:11812785).Curated
Sequence conflicti246 – 2461G → C in AAK93947 (PubMed:11812785).Curated
Sequence conflicti487 – 4871A → T in AAK93947 (PubMed:11812785).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC061865 mRNA. Translation: AAH61865.1.
AF236130 mRNA. Translation: AAK93947.1.
RefSeqiNP_619724.3. NM_138710.3.
UniGeneiRn.14323.

Genome annotation databases

EnsembliENSRNOT00000083134; ENSRNOP00000072901; ENSRNOG00000055226.
GeneIDi192126.
KEGGirno:192126.
UCSCiRGD:621686. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC061865 mRNA. Translation: AAH61865.1.
AF236130 mRNA. Translation: AAK93947.1.
RefSeqiNP_619724.3. NM_138710.3.
UniGeneiRn.14323.

3D structure databases

ProteinModelPortaliQ6P730.
SMRiQ6P730. Positions 113-463.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000056740.

PTM databases

iPTMnetiQ6P730.
PhosphoSiteiQ6P730.

Proteomic databases

PaxDbiQ6P730.
PRIDEiQ6P730.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000083134; ENSRNOP00000072901; ENSRNOG00000055226.
GeneIDi192126.
KEGGirno:192126.
UCSCiRGD:621686. rat.

Organism-specific databases

CTDi153090.
RGDi621686. Dab2ip.

Phylogenomic databases

eggNOGiKOG3508. Eukaryota.
ENOG410XPU1. LUCA.
GeneTreeiENSGT00760000119092.
HOGENOMiHOG000231979.
HOVERGENiHBG006492.
InParanoidiQ6P730.
KOiK19901.
OrthoDBiEOG74XS5P.

Enzyme and pathway databases

ReactomeiR-RNO-5658442. Regulation of RAS by GAPs.
R-RNO-8849471. PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.

Miscellaneous databases

PROiQ6P730.

Gene expression databases

GenevisibleiQ6P730. RN.

Family and domain databases

Gene3Di1.10.506.10. 1 hit.
2.60.40.150. 1 hit.
InterProiIPR000008. C2_dom.
IPR030403. DAB2IP.
IPR021887. DUF3498.
IPR023152. RasGAP_CS.
IPR001936. RasGAP_dom.
IPR008936. Rho_GTPase_activation_prot.
[Graphical view]
PANTHERiPTHR10194:SF26. PTHR10194:SF26. 1 hit.
PfamiPF00168. C2. 1 hit.
PF12004. DUF3498. 1 hit.
PF00616. RasGAP. 2 hits.
[Graphical view]
SMARTiSM00239. C2. 1 hit.
SM00323. RasGAP. 1 hit.
[Graphical view]
SUPFAMiSSF48350. SSF48350. 1 hit.
SSF49562. SSF49562. 1 hit.
PROSITEiPS00509. RAS_GTPASE_ACTIV_1. 1 hit.
PS50018. RAS_GTPASE_ACTIV_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "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: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 977-996, FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH DAB1 AND DAB2, MUTAGENESIS OF ARG-220.
    Tissue: Brain.
  2. NIH - Mammalian Gene Collection (MGC) project
    Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Prostate.
  3. "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-554, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].

Entry informationi

Entry nameiDAB2P_RAT
AccessioniPrimary (citable) accession number: Q6P730
Secondary accession number(s): Q924M9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 17, 2006
Last sequence update: July 5, 2004
Last modified: July 6, 2016
This is version 99 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

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. 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.