| Structural highlights
Function
DAB2_HUMAN 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.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Disabled-2 (Dab2) targets membranes and triggers a wide range of biological events, including endocytosis and platelet aggregation. Dab2, through its phosphotyrosine-binding (PTB) domain, inhibits platelet aggregation by competing with fibrinogen for alphaIIbbeta3 integrin receptor binding. We have recently shown that the N-terminal region, including the PTB domain (N-PTB), drives Dab2 to the platelet membrane surface by binding to sulfatides through two sulfatide-binding motifs, modulating the extent of platelet aggregation. The three-dimensional structure of a Dab2-derived peptide encompassing the sulfatide-binding motifs (SBM) has been determined in dodecylphosphocholine (DPC) micelles using NMR spectroscopy. Dab2 SBM contains two helices when embedded in micelles, reversibly binds to sulfatides with moderate affinity, lies parallel to the micelle surface, and, when added to a platelet mixture, reduces the number and size of sulfatide-induced aggregates. Overall, our findings identify and structurally characterize a minimal region in Dab2 that modulates platelet homotypic interactions, all of which provide the foundation for rational design of a new generation of anti-aggregatory low-molecular mass molecules for therapeutic purposes.
Structure, Sulfatide-binding Properties, and Inhibition of Platelet Aggregation by a Disabled-2-derived Peptide.,Xiao S, Charonko JJ, Fu X, Salmanzadeh A, Davalos RV, Vlachos PP, Finkielstein CV, Capelluto DG J Biol Chem. 2012 Sep 13. PMID:22977233[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. PMID:11387212 doi:http://dx.doi.org/10.1093/emboj/20.11.2789
- ↑ 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. PMID:12805222 doi:http://dx.doi.org/10.1093/emboj/cdg286
- ↑ 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. PMID:16267015 doi:http://dx.doi.org/10.1158/0008-5472.CAN-05-1481
- ↑ 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. Epub 2006 Sep 19. PMID:16984970 doi:http://dx.doi.org/10.1242/jcs.03217
- ↑ 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. PMID:19306879 doi:http://dx.doi.org/10.1016/j.febslet.2009.03.037
- ↑ 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. PMID:21995445 doi:http://dx.doi.org/10.1042/BJ20111566
- ↑ 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. PMID:22491013 doi:http://dx.doi.org/10.1038/emboj.2012.83
- ↑ 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. PMID:22323290 doi:http://dx.doi.org/10.1091/mbc.E11-09-0812
- ↑ Xiao S, Charonko JJ, Fu X, Salmanzadeh A, Davalos RV, Vlachos PP, Finkielstein CV, Capelluto DG. Structure, Sulfatide-binding Properties, and Inhibition of Platelet Aggregation by a Disabled-2-derived Peptide. J Biol Chem. 2012 Sep 13. PMID:22977233 doi:http://dx.doi.org/10.1074/jbc.M112.385609
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