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Dab2  -  disabled 2, mitogen-responsive phosphoprotein

Mus musculus

Synonyms: 5730435J12Rik, AA960054, AI957090, Adaptor molecule disabled-2, D15Wsu122e, ...
 
 
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Disease relevance of Dab2

  • In this study, the mouse Dab2 gene coding sequence was identified and sequenced from three lambda phage clones containing the gene [1].
  • Subsequently, the involvement of Dab2 in ovarian cancer development has been investigated: Dab2 expression is lost or greatly diminished in breast and ovarian cancers, and gene deletions have been found [1].
  • In contrast, p96 isoform mRNA levels were consistently decreased in mammary tumors derived from the in vivo hyperplasias [2].
 

High impact information on Dab2

  • Mouse embryo fibroblasts which lack Dab2 exhibit constitutive Wnt signaling as evidenced by increased levels of nuclear beta-catenin and cyclin D1 protein levels [3].
  • This evidence indicates that Dab2 is pleiotropic and regulates both visceral endoderm function and lipoprotein receptor trafficking in vivo [4].
  • In the absence of Dab2, embryos arrest prior to gastrulation with a phenotype reminiscent of those caused by deletion of some TGFbeta signal transduction molecules involved in Nodal signaling [4].
  • Moreover, our results revealed Dab2 as a novel IFN-gamma-response gene [5].
  • Furthermore, cell adhesion induces transient Dab2 phosphorylation and its translocation to the cytoskeletal/membrane fraction [5].
 

Biological context of Dab2

  • Overexpression of Dab2 leads to accelerated cell adhesion and spreading, accompanied by enhanced actin fiber formation [5].
  • 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 [6].
  • Surprisingly, the specificity of GATA-6-induced transactivation of the Dab2 promoter is not mediated through its zinc finger DNA-binding domain [7].
  • We suggest that Dab2 functions in a signal pathway to regulate endodermal cell organization using endocytosis of ligands from the blastocoel cavity as a positioning cue [8].
  • Our findings indicate that Dab2 plays an important regulatory role during cellular differentiation and that induction of differentiation in the absence of Dab2 expression commits the cell to apoptosis [9].
 

Anatomical context of Dab2

 

Associations of Dab2 with chemical compounds

  • Forced re-expression of human Dab2, not targeted by the mouse siRNA sequence, rescues cells from apoptosis and restores TGFbeta-mediated integrin activation and EMT [9].
  • These data indicate that Dab2 binds to the SH3 domains of Grb2 via its C-terminal proline-rich sequences [12].
  • Metabolic labeling experiments showed that the gel retardation of p96 was associated with increased phosphorylation of the protein exclusively on serine residues [13].
  • In contrast to the other Doc2 isoforms, the C2 domains of Doc2gamma impair Ca(2+)-dependent phospholipid binding activity [14].
  • Unlike p96, p67 largely resides in RA-treated F9 cell nuclei [15].
 

Physical interactions of Dab2

  • Disabled-2 (Dab2) is a cytoplasmic adaptor protein that binds to the cytoplasmic tail of the multiligand endocytic receptor megalin, abundantly expressed in renal proximal tubules [16].
 

Co-localisations of Dab2

 

Regulatory relationships of Dab2

  • Here, we have demonstrated that TGFbeta induces the expression of the adaptor molecule disabled-2 (Dab2) concomitant with the promotion of EMT [9].
  • This study revealed that the sites, where Dab2 is downregulated in the mutant embryos partly overlap with the Gata3 expression domains, including the mid-embryo region, branchial arches and facio-acoustic (VII-VIII) neural crest complex [17].
 

Other interactions of Dab2

  • Taken together, these data demonstrate that the mitogen-responsive phosphoprotein Dab2 is a downstream target of GATA-6 in the visceral endoderm [7].
  • These studies suggest that Dab2 p96 mediates endocytosis of megalin in the VE [10].
  • The homozygous Dab2-deficient mutant is embryonic lethal (earlier than E6.5) due to defective cell positioning and structure formation of the visceral endoderm [8].
  • This is the first time when tumor supressor gene Dab2 is shown to be implicated in the defective phenotype of Gata3 mutant mice [17].
  • Endocytosis of cubilin is also impaired in VE and in mid-gestation visceral yolk sac when p96 is absent [10].
 

Analytical, diagnostic and therapeutic context of Dab2

  • Polypeptide analysis of the purified gbLOX by SDS-PAGE detected two distinct polypeptides (p96 and p94), which were identical to LOX-3 as determined by their partial N-terminal amino acid sequences [18].

References

  1. Chromosomal location of murine disabled-2 gene and structural comparison with its human ortholog. Sheng, Z., Smith, E.R., He, J., Tuppen, J.A., Martin, W.D., Dong, F.B., Xu, X.X. Gene (2001) [Pubmed]
  2. p96, a MAPK-related protein, is consistently downregulated during mouse mammary carcinogenesis. Schwahn, D.J., Medina, D. Oncogene (1998) [Pubmed]
  3. Regulation of the Wnt signaling pathway by disabled-2 (Dab2). Hocevar, B.A., Mou, F., Rennolds, J.L., Morris, S.M., Cooper, J.A., Howe, P.H. EMBO J. (2003) [Pubmed]
  4. Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport. Morris, S.M., Tallquist, M.D., Rock, C.O., Cooper, J.A. EMBO J. (2002) [Pubmed]
  5. Disabled-2 is transcriptionally regulated by ICSBP and augments macrophage spreading and adhesion. Rosenbauer, F., Kallies, A., Scheller, M., Knobeloch, K.P., Rock, C.O., Schwieger, M., Stocking, C., Horak, I. EMBO J. (2002) [Pubmed]
  6. Crystal structures of the Dab homology domains of mouse disabled 1 and 2. Yun, M., Keshvara, L., Park, C.G., Zhang, Y.M., Dickerson, J.B., Zheng, J., Rock, C.O., Curran, T., Park, H.W. J. Biol. Chem. (2003) [Pubmed]
  7. The gene encoding the mitogen-responsive phosphoprotein Dab2 is differentially regulated by GATA-6 and GATA-4 in the visceral endoderm. Morrisey, E.E., Musco, S., Chen, M.Y., Lu, M.M., Leiden, J.M., Parmacek, M.S. J. Biol. Chem. (2000) [Pubmed]
  8. Disabled-2 is essential for endodermal cell positioning and structure formation during mouse embryogenesis. Yang, D.H., Smith, E.R., Roland, I.H., Sheng, Z., He, J., Martin, W.D., Hamilton, T.C., Lambeth, J.D., Xu, X.X. Dev. Biol. (2002) [Pubmed]
  9. Disabled-2 (Dab2) is required for transforming growth factor beta-induced epithelial to mesenchymal transition (EMT). Prunier, C., Howe, P.H. J. Biol. Chem. (2005) [Pubmed]
  10. Endocytosis of megalin by visceral endoderm cells requires the Dab2 adaptor protein. Maurer, M.E., Cooper, J.A. J. Cell. Sci. (2005) [Pubmed]
  11. Disabled-2 heterozygous mice are predisposed to endometrial and ovarian tumorigenesis and exhibit sex-biased embryonic lethality in a p53-null background. Yang, D.H., Fazili, Z., Smith, E.R., Cai, K.Q., Klein-Szanto, A., Cohen, C., Horowitz, I.R., Xu, X.X. Am. J. Pathol. (2006) [Pubmed]
  12. Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2. Xu, X.X., Yi, T., Tang, B., Lambeth, J.D. Oncogene (1998) [Pubmed]
  13. Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product. Xu, X.X., Yang, W., Jackowski, S., Rock, C.O. J. Biol. Chem. (1995) [Pubmed]
  14. Doc2gamma, a third isoform of double C2 protein, lacking calcium-dependent phospholipid binding activity. Fukuda, M., Mikoshiba, K. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  15. p67 isoform of mouse disabled 2 protein acts as a transcriptional activator during the differentiation of F9 cells. Cho, S.Y., Jeon, J.W., Lee, S.H., Park, S.S. Biochem. J. (2000) [Pubmed]
  16. Mutually dependent localization of megalin and Dab2 in the renal proximal tubule. Nagai, J., Christensen, E.I., Morris, S.M., Willnow, T.E., Cooper, J.A., Nielsen, R. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  17. Gene expression analysis of Gata3-/- mice by using cDNA microarray technology. Airik, R., Kärner, M., Karis, A., Kärner, J. Life Sci. (2005) [Pubmed]
  18. Physiological correlation between glycyrrhizin, glycyrrhizin-binding lipoxygenase and casein kinase II. Shimoyama, Y., Ohtaka, H., Nagata, N., Munakata, H., Hayashi, N., Ohtsuki, K. FEBS Lett. (1996) [Pubmed]
 
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