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Identification
HMDB Protein ID HMDBP14533
Secondary Accession Numbers None
Name Disabled homolog 2
Synonyms
  1. Adaptor molecule disabled-2
  2. Differentially expressed in ovarian carcinoma 2
  3. Differentially-expressed protein 2
  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. 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.
Pathways
  • Endocytosis
Reactions Not Available
GO Classification
Biological Process
multicellular organismal development
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
membrane organization
protein transport
positive regulation of early endosome to late endosome transport
positive regulation of pathway-restricted SMAD protein phosphorylation
positive regulation of epithelial to mesenchymal transition
positive regulation of protein phosphorylation
Wnt receptor signaling pathway
positive regulation of Wnt signaling pathway, planar cell polarity pathway
positive regulation of endocytosis
negative regulation of transcription from RNA polymerase II promoter
positive regulation of transcription from RNA polymerase II promoter
negative regulation of canonical Wnt receptor signaling pathway
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
positive regulation of clathrin-dependent endocytosis
receptor-mediated endocytosis
negative regulation of androgen receptor signaling pathway
Cellular Component
cytosol
focal adhesion
cytoplasm
plasma membrane
clathrin-coated vesicle
coated pit
fibrillar center
clathrin-coated vesicle membrane
lysosomal membrane
intracellular membrane-bounded organelle
Molecular Function
protein C-terminus binding
cargo receptor activity
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 770
Molecular Weight 82447.215
Theoretical pI 5.533
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID P98082
UniProtKB/Swiss-Prot Entry Name DAB2_HUMAN
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. [PubMed:18669648 ]
  3. Gauci S, Helbig AO, Slijper M, Krijgsveld J, Heck AJ, Mohammed S: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal Chem. 2009 Jun 1;81(11):4493-501. doi: 10.1021/ac9004309. [PubMed:19413330 ]
  4. Beausoleil SA, Villen J, Gerber SA, Rush J, Gygi SP: A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol. 2006 Oct;24(10):1285-92. Epub 2006 Sep 10. [PubMed:16964243 ]
  5. Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S, Gordon LA, Scott D, Xie G, Huang W, Hellsten U, Tran-Gyamfi M, She X, Prabhakar S, Aerts A, Altherr M, Bajorek E, Black S, Branscomb E, Caoile C, Challacombe JF, Chan YM, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Lopez F, Lou Y, Martinez D, Medina C, Morgan J, Nandkeshwar R, Noonan JP, Pitluck S, Pollard M, Predki P, Priest J, Ramirez L, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wheeler J, Wu K, Yang J, Dickson M, Cheng JF, Eichler EE, Olsen A, Pennacchio LA, Rokhsar DS, Richardson P, Lucas SM, Myers RM, Rubin EM: The DNA sequence and comparative analysis of human chromosome 5. Nature. 2004 Sep 16;431(7006):268-74. [PubMed:15372022 ]
  6. Morris SM, Arden SD, Roberts RC, Kendrick-Jones J, Cooper JA, Luzio JP, Buss F: Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton. Traffic. 2002 May;3(5):331-41. [PubMed:11967127 ]
  7. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. [PubMed:20068231 ]
  8. Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S: Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013 Jan 4;12(1):260-71. doi: 10.1021/pr300630k. Epub 2012 Dec 18. [PubMed:23186163 ]
  9. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. [PubMed:21269460 ]
  10. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. [PubMed:24275569 ]
  11. Umasankar PK, Sanker S, Thieman JR, Chakraborty S, Wendland B, Tsang M, Traub LM: Distinct and separable activities of the endocytic clathrin-coat components Fcho1/2 and AP-2 in developmental patterning. Nat Cell Biol. 2012 Apr 8;14(5):488-501. doi: 10.1038/ncb2473. [PubMed:22484487 ]
  12. Hocevar BA, Smine A, Xu XX, Howe PH: The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway. EMBO J. 2001 Jun 1;20(11):2789-801. doi: 10.1093/emboj/20.11.2789. [PubMed:11387212 ]
  13. Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH: Regulation of the Wnt signaling pathway by disabled-2 (Dab2). EMBO J. 2003 Jun 16;22(12):3084-94. doi: 10.1093/emboj/cdg286. [PubMed:12805222 ]
  14. Chetrit D, Barzilay L, Horn G, Bielik T, Smorodinsky NI, Ehrlich M: Negative regulation of the endocytic adaptor disabled-2 (Dab2) in mitosis. J Biol Chem. 2011 Feb 18;286(7):5392-403. doi: 10.1074/jbc.M110.161851. Epub 2010 Nov 19. [PubMed:21097498 ]
  15. Albertsen HM, Smith SA, Melis R, Williams B, Holik P, Stevens J, White R: Sequence, genomic structure, and chromosomal assignment of human DOC-2. Genomics. 1996 Apr 15;33(2):207-13. doi: 10.1006/geno.1996.0185. [PubMed:8660969 ]
  16. Mok SC, Chan WY, Wong KK, Cheung KK, Lau CC, Ng SW, Baldini A, Colitti CV, Rock CO, Berkowitz RS: DOC-2, a candidate tumor suppressor gene in human epithelial ovarian cancer. Oncogene. 1998 May 7;16(18):2381-7. doi: 10.1038/sj.onc.1201769. [PubMed:9620555 ]
  17. Fazili Z, Sun W, Mittelstaedt S, Cohen C, Xu XX: Disabled-2 inactivation is an early step in ovarian tumorigenicity. Oncogene. 1999 May 20;18(20):3104-13. doi: 10.1038/sj.onc.1202649. [PubMed:10340382 ]
  18. Mok SC, Wong KK, Chan RK, Lau CC, Tsao SW, Knapp RC, Berkowitz RS: Molecular cloning of differentially expressed genes in human epithelial ovarian cancer. Gynecol Oncol. 1994 Feb;52(2):247-52. doi: 10.1006/gyno.1994.1040. [PubMed:8314147 ]
  19. Oleinikov AV, Zhao J, Makker SP: Cytosolic adaptor protein Dab2 is an intracellular ligand of endocytic receptor gp600/megalin. Biochem J. 2000 May 1;347 Pt 3:613-21. [PubMed:10769163 ]
  20. 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 ]
  21. Gallagher H, Oleinikov AV, Fenske C, Newman DJ: The adaptor disabled-2 binds to the third psi xNPxY sequence on the cytoplasmic tail of megalin. Biochimie. 2004 Mar;86(3):179-82. doi: 10.1016/j.biochi.2004.03.001. [PubMed:15134832 ]
  22. Zhoul J, Hernandez G, Tu SW, Huang CL, Tseng CP, Hsieh JT: The role of DOC-2/DAB2 in modulating androgen receptor-mediated cell growth via the nongenomic c-Src-mediated pathway in normal prostatic epithelium and cancer. Cancer Res. 2005 Nov 1;65(21):9906-13. doi: 10.1158/0008-5472.CAN-05-1481. [PubMed:16267015 ]
  23. 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 ]
  24. Chao WT, Kunz J: Focal adhesion disassembly requires clathrin-dependent endocytosis of integrins. FEBS Lett. 2009 Apr 17;583(8):1337-43. doi: 10.1016/j.febslet.2009.03.037. Epub 2009 Mar 22. [PubMed:19306879 ]
  25. Fu L, Rab A, Tang LP, Rowe SM, Bebok Z, Collawn JF: Dab2 is a key regulator of endocytosis and post-endocytic trafficking of the cystic fibrosis transmembrane conductance regulator. Biochem J. 2012 Jan 15;441(2):633-43. doi: 10.1042/BJ20111566. [PubMed:21995445 ]
  26. Jiang Y, He X, Howe PH: Disabled-2 (Dab2) inhibits Wnt/beta-catenin signalling by binding LRP6 and promoting its internalization through clathrin. EMBO J. 2012 May 16;31(10):2336-49. doi: 10.1038/emboj.2012.83. Epub 2012 Apr 10. [PubMed:22491013 ]