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MGP000778

UniProt Annotations

Entry Information

Gene Name	Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila)
Protein Entry	DAB2_HUMAN
UniProt ID	P98082
Species	Human

Comments

Comment type	Description
Alternative Products	Event=Alternative splicing; Named isoforms=3; Name=1; IsoId=P98082-1; Sequence=Displayed; Name=2; IsoId=P98082-2; Sequence=VSP_004181; Name=3; IsoId=P98082-3; Sequence=VSP_038401;
Domain	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. {ECO:0000250}.
Domain	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. {ECO:0000250}.
Function	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. {ECO:0000269\|PubMed:11387212, ECO:0000269\|PubMed:12805222, ECO:0000269\|PubMed:16267015, ECO:0000269\|PubMed:16984970, ECO:0000269\|PubMed:19306879, ECO:0000269\|PubMed:21995445, ECO:0000269\|PubMed:22323290, ECO:0000269\|PubMed:22491013}.
Interaction	P62993:GRB2; NbExp=2; IntAct=EBI-1171238, EBI-401755; O75581:LRP6; NbExp=20; IntAct=EBI-1171238, EBI-910915; Q9UM54:MYO6; NbExp=3; IntAct=EBI-1171238, EBI-350606; P16333:NCK1; NbExp=2; IntAct=EBI-1171238, EBI-389883; Q15796:SMAD2; NbExp=4; IntAct=EBI-1171238, EBI-1040141; P84022:SMAD3; NbExp=3; IntAct=EBI-1171238, EBI-347161;
Ptm	Phosphorylated. Phosphorylation during mitosis is leading to membrane displacement (By similarity). {ECO:0000250}.
Similarity	Contains 1 PID domain. {ECO:0000255\|PROSITE- ProRule:PRU00148}.
Subcellular Location	Cytoplasm. Cytoplasmic vesicle, clathrin- coated vesicle membrane. Membrane, clathrin-coated pit. Note=Colocalizes with large insert-containing isoforms of MYO6 at clathrin-coated pits/vesicles. During mitosis is progressively displaced from the membrane and translocated to the cytoplasm.
Subunit	Interacts (via NPXY motif) with DAB2 (via PID domain). 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. {ECO:0000269\|PubMed:10769163, ECO:0000269\|PubMed:11387212, ECO:0000269\|PubMed:11967127, ECO:0000269\|PubMed:12805222, ECO:0000269\|PubMed:14596919, ECO:0000269\|PubMed:15134832, ECO:0000269\|PubMed:22323290, ECO:0000269\|PubMed:22484487, ECO:0000269\|PubMed:22491013, ECO:0000305}.
Tissue Specificity	Expressed in deep invaginations, inclusion cysts and the surface epithelial cells of the ovary. Also expressed in breast epithelial cells, spleen, thymus, prostate, testis, macrophages, fibroblasts, lung epithelial cells, placenta, brain stem, heart and small intestine. Expressed in kidney proximal tubular epithelial cells (at protein level). {ECO:0000269\|PubMed:10340382, ECO:0000269\|PubMed:15134832, ECO:0000269\|PubMed:9620555}.
Web Resource	Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/DAB2ID40258ch5p13.html";