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Identification
HMDB Protein ID HMDBP14539
Secondary Accession Numbers None
Name Disabled homolog 2
Synonyms
  1. Adaptor molecule disabled-2
  2. Differentially expressed in ovarian carcinoma 2
  3. Mitogen-responsive phosphoprotein
  4. DOC-2
Gene Name DAB2
Protein Type Unknown
Biological Properties
General Function Not Available
Specific 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 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. Isoform p96 is involved in endocytosis of megalin/LRP2 lipoprotein receptor during embryonal development. Required for recycling of the TGF-beta receptor. Isoform p67 is not involved in LDL receptor endocytosis. 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. Isoform p67 may be involved in transcriptional regulation. May act as a tumor suppressor.
Pathways
  • Endocytosis
Reactions Not Available
GO Classification
Biological Process
pinocytosis
positive regulation of transcription elongation from RNA polymerase II promoter
positive regulation of cell migration
leading edge cell differentiation
apoptotic process
positive regulation of proteasomal ubiquitin-dependent protein catabolic process
negative regulation of apoptotic process
positive regulation of cell adhesion
protein transport
positive regulation of early endosome to late endosome transport
negative regulation of epithelial cell proliferation
in utero embryonic development
negative regulation of extrinsic apoptotic signaling pathway
positive regulation of pathway-restricted SMAD protein phosphorylation
positive regulation of epithelial to mesenchymal transition
positive regulation of protein phosphorylation
positive regulation of integrin-mediated signaling pathway
activation of JUN kinase activity
Wnt receptor signaling pathway
positive regulation of Wnt signaling pathway, planar cell polarity pathway
positive regulation of endocytosis
cellular response to epidermal growth factor stimulus
negative regulation of transcription from RNA polymerase II promoter
endoderm development
positive regulation of transcription from RNA polymerase II promoter
negative regulation of canonical Wnt receptor signaling pathway
negative regulation of neuron projection development
negative regulation of cell growth
positive regulation of receptor internalization
positive regulation of aldosterone biosynthetic process
positive regulation of aldosterone secretion
response to steroid hormone stimulus
positive regulation of SMAD protein signal transduction
negative regulation of protein localization to plasma membrane
positive regulation of transforming growth factor beta receptor signaling pathway
negative regulation of protein binding
negative regulation of ERK1 and ERK2 cascade
cellular response to transforming growth factor beta stimulus
excretion
cell morphogenesis involved in differentiation
clathrin coat assembly
hematopoietic stem cell proliferation
positive regulation of clathrin-dependent endocytosis
regulation of Rho-dependent protein serine/threonine kinase activity
receptor-mediated endocytosis
myeloid cell differentiation
negative regulation of androgen receptor signaling pathway
positive regulation of substrate adhesion-dependent cell spreading
positive regulation of receptor recycling
Cellular Component
cytoplasm
plasma membrane
perinuclear region of cytoplasm
nucleus
clathrin-coated vesicle
coated pit
fibrillar center
apical plasma membrane
clathrin coat of coated pit
clathrin-coated vesicle membrane
intracellular membrane-bounded organelle
Molecular Function
protein C-terminus binding
phosphatidylinositol binding
phosphatidylinositol-4,5-bisphosphate binding
integrin binding
clathrin binding
AP-2 adaptor complex binding
cargo receptor activity
low-density lipoprotein particle receptor binding
clathrin adaptor activity
SMAD binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 766
Molecular Weight 82311.215
Theoretical pI 6.099
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID P98078
UniProtKB/Swiss-Prot Entry Name DAB2_MOUSE
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
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  4. Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villen J, Haas W, Sowa ME, Gygi SP: A tissue-specific atlas of mouse protein phosphorylation and expression. Cell. 2010 Dec 23;143(7):1174-89. doi: 10.1016/j.cell.2010.12.001. [PubMed:21183079 ]
  5. Trost M, English L, Lemieux S, Courcelles M, Desjardins M, Thibault P: The phagosomal proteome in interferon-gamma-activated macrophages. Immunity. 2009 Jan 16;30(1):143-54. doi: 10.1016/j.immuni.2008.11.006. [PubMed:19144319 ]
  6. Xu XX, Yi T, Tang B, Lambeth JD: Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2. Oncogene. 1998 Mar 26;16(12):1561-9. doi: 10.1038/sj.onc.1201678. [PubMed:9569023 ]
  7. Kowanetz K, Terzic J, Dikic I: Dab2 links CIN85 with clathrin-mediated receptor internalization. FEBS Lett. 2003 Nov 6;554(1-2):81-7. doi: 10.1016/s0014-5793(03)01111-6. [PubMed:14596919 ]
  8. Maurer ME, Cooper JA: The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH. J Cell Sci. 2006 Oct 15;119(Pt 20):4235-46. doi: 10.1242/jcs.03217. Epub 2006 Sep 19. [PubMed:16984970 ]
  9. Xu XX, Yang W, Jackowski S, Rock CO: Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product. J Biol Chem. 1995 Jun 9;270(23):14184-91. doi: 10.1074/jbc.270.23.14184. [PubMed:7775479 ]
  10. Sheng Z, Smith ER, He J, Tuppen JA, Martin WD, Dong FB, Xu XX: Chromosomal location of murine disabled-2 gene and structural comparison with its human ortholog. Gene. 2001 May 2;268(1-2):31-9. doi: 10.1016/s0378-1119(01)00401-2. [PubMed:11368898 ]
  11. Cho SY, Jeon JW, Lee SH, Park SS: p67 isoform of mouse disabled 2 protein acts as a transcriptional activator during the differentiation of F9 cells. Biochem J. 2000 Dec 15;352 Pt 3:645-50. [PubMed:11104669 ]
  12. Morris SM, Cooper JA: Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2. Traffic. 2001 Feb;2(2):111-23. doi: 10.1034/j.1600-0854.2001.020206.x. [PubMed:11247302 ]
  13. Inoue A, Sato O, Homma K, Ikebe M: DOC-2/DAB2 is the binding partner of myosin VI. Biochem Biophys Res Commun. 2002 Mar 29;292(2):300-7. doi: 10.1006/bbrc.2002.6636. [PubMed:11906161 ]
  14. Rosenbauer F, Kallies A, Scheller M, Knobeloch KP, Rock CO, Schwieger M, Stocking C, Horak I: Disabled-2 is transcriptionally regulated by ICSBP and augments macrophage spreading and adhesion. EMBO J. 2002 Feb 1;21(3):211-20. doi: 10.1093/emboj/21.3.211. [PubMed:11823414 ]
  15. Morris SM, Tallquist MD, Rock CO, Cooper JA: Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport. EMBO J. 2002 Apr 2;21(7):1555-64. doi: 10.1093/emboj/21.7.1555. [PubMed:11927540 ]
  16. Mishra SK, Keyel PA, Hawryluk MJ, Agostinelli NR, Watkins SC, Traub LM: Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor. EMBO J. 2002 Sep 16;21(18):4915-26. doi: 10.1093/emboj/cdf487. [PubMed:12234931 ]
  17. Homayouni R, Magdaleno S, Keshvara L, Rice DS, Curran T: Interaction of Disabled-1 and the GTPase activating protein Dab2IP in mouse brain. Brain Res Mol Brain Res. 2003 Jul 23;115(2):121-9. doi: 10.1016/s0169-328x(03)00176-1. [PubMed:12877983 ]
  18. Calderwood DA, Fujioka Y, de Pereda JM, Garcia-Alvarez B, Nakamoto T, Margolis B, McGlade CJ, Liddington RC, Ginsberg MH: Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2272-7. doi: 10.1073/pnas.262791999. Epub 2003 Feb 26. [PubMed:12606711 ]
  19. Choi YJ, Cho SY, Kim HW, Kim JA, Bae SH, Park SS: Cloning and characterization of mouse disabled 2 interacting protein 2, a mouse orthologue of human NOSTRIN. Biochem Biophys Res Commun. 2005 Jan 21;326(3):594-9. doi: 10.1016/j.bbrc.2004.11.079. [PubMed:15596140 ]
  20. Prunier C, Howe PH: Disabled-2 (Dab2) is required for transforming growth factor beta-induced epithelial to mesenchymal transition (EMT). J Biol Chem. 2005 Apr 29;280(17):17540-8. doi: 10.1074/jbc.M500974200. Epub 2005 Feb 25. [PubMed:15734730 ]
  21. Hocevar BA, Prunier C, Howe PH: Disabled-2 (Dab2) mediates transforming growth factor beta (TGFbeta)-stimulated fibronectin synthesis through TGFbeta-activated kinase 1 and activation of the JNK pathway. J Biol Chem. 2005 Jul 8;280(27):25920-7. doi: 10.1074/jbc.M501150200. Epub 2005 May 12. [PubMed:15894542 ]
  22. Maurer ME, Cooper JA: Endocytosis of megalin by visceral endoderm cells requires the Dab2 adaptor protein. J Cell Sci. 2005 Nov 15;118(Pt 22):5345-55. doi: 10.1242/jcs.02650. Epub 2005 Nov 1. [PubMed:16263760 ]
  23. Keyel PA, Mishra SK, Roth R, Heuser JE, Watkins SC, Traub LM: A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors. Mol Biol Cell. 2006 Oct;17(10):4300-17. doi: 10.1091/mbc.e06-05-0421. Epub 2006 Jul 26. [PubMed:16870701 ]
  24. Jiang Y, Luo W, Howe PH: Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions. Oncogene. 2009 Aug 20;28(33):2999-3007. doi: 10.1038/onc.2009.157. Epub 2009 Jul 6. [PubMed:19581931 ]
  25. Mulkearns EE, Cooper JA: FCH domain only-2 organizes clathrin-coated structures and interacts with Disabled-2 for low-density lipoprotein receptor endocytosis. Mol Biol Cell. 2012 Apr;23(7):1330-42. doi: 10.1091/mbc.E11-09-0812. Epub 2012 Feb 9. [PubMed:22323290 ]
  26. Teckchandani A, Mulkearns EE, Randolph TW, Toida N, Cooper JA: The clathrin adaptor Dab2 recruits EH domain scaffold proteins to regulate integrin beta1 endocytosis. Mol Biol Cell. 2012 Aug;23(15):2905-16. doi: 10.1091/mbc.E11-12-1007. Epub 2012 May 30. [PubMed:22648170 ]
  27. Yun M, Keshvara L, Park CG, Zhang YM, Dickerson JB, Zheng J, Rock CO, Curran T, Park HW: Crystal structures of the Dab homology domains of mouse disabled 1 and 2. J Biol Chem. 2003 Sep 19;278(38):36572-81. doi: 10.1074/jbc.M304384200. Epub 2003 Jun 24. [PubMed:12826668 ]