| Structural highlights
Function
[DAB2_MOUSE] 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. 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Disabled (Dab) 1 and 2 are mammalian homologues of Drosophila DAB. Dab1 is a key cytoplasmic mediator in Reelin signaling that controls cell positioning in the developing central nervous system, whereas Dab2 is an adapter protein that plays a role in endocytosis. DAB family proteins possess an amino-terminal DAB homology (DH) domain that is similar to the phosphotyrosine binding/phosphotyrosine interaction (PTB/PI) domain. We have solved the structures of the DH domains of Dab2 (Dab2-DH) and Dab1 (Dab1-DH) in three different ligand forms, ligand-free Dab2-DH, the binary complex of Dab2-DH with the Asn-Pro-X-Tyr (NPXY) peptide of amyloid precursor protein (APP), and the ternary complex of Dab1-DH with the APP peptide and inositol 1,4,5-trisphosphate (Ins-1,4,5-P3, the head group of phosphatidylinositol-4,5-diphosphate (PtdIns-4,5-P2)). The similarity of these structures suggests that the rigid Dab DH domain maintains two independent pockets for binding of the APP/lipoprotein receptors and phosphoinositides. Mutagenesis confirmed the structural determinants specific for the NPXY sequence and PtdIns-4,5-P2 binding. NMR spectroscopy confirmed that the DH domain binds to Ins-1,4,5-P3 independent of the NPXY peptides. These findings suggest that simultaneous interaction of the rigid DH domain with the NPXY sequence and PtdIns-4,5-P2 plays a role in the attachment of Dab proteins to the APP/lipoprotein receptors and phosphoinositide-rich membranes.
Crystal structures of the Dab homology domains of mouse disabled 1 and 2.,Yun M, Keshvara L, Park CG, Zhang YM, Dickerson JB, Zheng J, Rock CO, Curran T, Park HW J Biol Chem. 2003 Sep 19;278(38):36572-81. Epub 2003 Jun 24. PMID:12826668[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. PMID:11104669
- ↑ 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. PMID:11247302
- ↑ Yang DH, Smith ER, Roland IH, Sheng Z, He J, Martin WD, Hamilton TC, Lambeth JD, Xu XX. Disabled-2 is essential for endodermal cell positioning and structure formation during mouse embryogenesis. Dev Biol. 2002 Nov 1;251(1):27-44. PMID:12413896
- ↑ 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. PMID:11823414 doi:http://dx.doi.org/10.1093/emboj/21.3.211
- ↑ 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. PMID:11927540 doi:http://dx.doi.org/10.1093/emboj/21.7.1555
- ↑ 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. PMID:12234931
- ↑ 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. Epub 2005 Feb 25. PMID:15734730 doi:http://dx.doi.org/10.1074/jbc.M500974200
- ↑ 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. Epub 2005 May 12. PMID:15894542 doi:http://dx.doi.org/10.1074/jbc.M501150200
- ↑ 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. Epub 2005 Nov 1. PMID:16263760 doi:http://dx.doi.org/10.1242/jcs.02650
- ↑ 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
- ↑ 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. Epub 2006 Jul 26. PMID:16870701 doi:http://dx.doi.org/10.1091/mbc.E06-05-0421
- ↑ 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. PMID:19581931 doi:http://dx.doi.org/10.1038/onc.2009.157
- ↑ Penheiter SG, Singh RD, Repellin CE, Wilkes MC, Edens M, Howe PH, Pagano RE, Leof EB. Type II transforming growth factor-beta receptor recycling is dependent upon the clathrin adaptor protein Dab2. Mol Biol Cell. 2010 Nov 15;21(22):4009-19. doi: 10.1091/mbc.E09-12-1019. Epub, 2010 Sep 29. PMID:20881059 doi:http://dx.doi.org/10.1091/mbc.E09-12-1019
- ↑ 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. Epub 2003 Jun 24. PMID:12826668 doi:10.1074/jbc.M304384200
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