Alternative titles; symbols
HGNC Approved Gene Symbol: DAB2
Cytogenetic location: 5p13.1 Genomic coordinates (GRCh38): 5:39,371,677-39,424,980 (from NCBI)
Mok et al. (1994) used a PCR-based differential display method to identify genes expressed in ovarian cancer (167000). Two cDNAs, termed DOC1 and DOC2 by them, were identified that were expressed in normal ovarian epithelial cells but were downregulated or absent from ovarian carcinoma cell lines. Albertsen et al. (1996) determined the complete sequence of the 3.2-kb DOC2 cDNA. They also cloned a genomic fragment at the 5-prime end of the gene which includes exons 1 to 8. The 770-amino acid predicted protein has an overall 83% identity with the mouse p96 protein, a putative mitogen-responsive phosphoprotein; homology is strongest in the amino-terminal end of the protein in a region corresponding to the phosphotyrosine interaction domain. The mouse p96 protein is phosphorylated on serine residues rather than tyrosines; phosphorylation is lowest in the G1 cell cycle stage but rapidly increases following mitogenic stimulation with colony stimulating factor (120420)(Xu et al., 1995). Albertsen et al. (1996) stated that DOC2 is expressed in at least 7 different human tissues and that it and its murine homolog are likely expressed in a tissue-independent manner.
Sheng et al. (2001) determined that the mouse and human DAB2 genes have highly similar structures, consisting of 15 exons that span about 40 kb. The first exon is untranslated, and the first intron is unusually large (about 15 kb). The human and mouse genes also share similarity in the 5-prime region of intron 1.
Albertsen et al. (1996) mapped the DOC2 gene to 5p13 by fluorescence in situ hybridization and confirmed the mapping through analysis of a human/rodent somatic cell hybrid mapping panel. By FISH, Sheng et al. (2001) mapped the mouse Dab2 gene to chromosome 15A2 in a region that shows homology of synteny to human chromosome 5p12.
Mok et al. (1998) reported that when DOC2 was transfected into an ovarian carcinoma cell line, the stable transfectants showed significantly reduced growth rate and ability to form tumors in nude mice.
Xu et al. (1998) found evidence that DAB2 interacts with GRB2 (108355), an adaptor protein that couples tyrosine kinase receptors to SOS (182530). By coimmunoprecipitation of a mouse macrophage-like cell line, they found that significant quantities of Grb2 were associated with both Sos and Dab2, although Sos and Dab2 were not present in the same complexes. Further examination indicated that DAB2 competes with SOS for GRB2 binding. Using truncation mutants, Xu et al. (1998) determined that the interaction required the C-terminal proline-rich region of Dab2 and both SH3 domains of Grb2.
Hocevar et al. (2001) developed a human fibrosarcoma cell line that was deficient in transforming growth factor-beta (TGFB; 190180) signaling. They found that the mutant cells harbored a missense mutation in the C-terminal domain of DAB2, resulting in decreased stability and steady-state expression of DAB2. Restoration of stable expression of DAB2 restored all assayed TGFB responses, including SMAD2 (601366) phosphorylation, SMAD nuclear translocation, and SMAD transcriptional activity. DAB2 associated with SMAD2 and SMAD3 (603109) in a time- and ligand-dependent manner, and this association was mediated by direct interaction between the N-terminal phosphotyrosine-binding domain of DAB2 and the MH2 domains of SMAD2 and SMAD3. Mutation analysis indicated that both the phosphotyrosine-binding domain and the C-terminal proline-rich domain of DAB2 were required for TGFB signaling. DAB2 also associated with TGFB receptor I (TGFBR1; 604616) and TGFBR2 (604615), suggesting that it is part of a multiprotein signaling complex.
Rosenbauer et al. (2002) demonstrated differential transcription of mouse Dab2 in myeloid cells developed from Icsbp (601565) -/- and Icsbp +/+ mice. Dab2 transcription and protein expression were repressed in Icsbp +/+ cells in response to gamma-interferon (IFNG; 147570), and DNA affinity binding revealed Icsbp recruitment to the Dab2 promoter after IFNG induction. The PU.1 transcription factor (SPI1; 165170) also bound to the Dab2 promoter, and Icsbp repressed PU.1-induced Dab2 promoter transactivation in vitro. Overexpression of Dab2 led to accelerated cell adhesion and spreading and was accompanied by enhanced actin fiber formation. Cell adhesion induced transient Dab2 phosphorylation and its accumulation in the cytoskeletal/membrane fraction.
By yeast 2-hybrid analysis, Inoue et al. (2002) demonstrated interaction between the C-terminal 122 amino acids of mouse Dab2, containing the Grb2-binding site, and the tail domain of human myosin VI (MYO6; 600970). The interaction showed 1:1 stoichiometry. Actin gliding assays revealed that binding of Dab2 to Myo6 enhanced actin filament gliding by Myo6. The N terminus of Dab2 did not affect actin gliding.
Zhou et al. (2003) found direct interaction between the SH3 domain of SRC (190090), a nonreceptor tyrosine kinase, with the first proline-rich domain of DAB2. Binding between these proteins was enhanced in human prostate cancer cells treated with EGF (131530). Interaction led to the inhibition of tyr416 phosphorylation of SRC and reduced downstream effector activation.
Eden et al. (2007) found that siRNA depletion of DAB2 resulted in almost complete loss of LDL-receptor protein (LDLRAP1; 605747), but not mRNA, in fibroblasts from patients with autosomal recessive hypercholesterolemia (ARH; 603813) but not controls; heterologous expression of murine Dab2 reversed this effect. Incorporation of radiolabeled amino acids into LDL receptor protein revealed a corresponding apparent reduction in accumulation of newly synthesized LDL-receptor protein upon depletion of DAB2 in ARH cells, but not in control cells. The reduction in LDL-receptor protein in DAB2-depleted ARH cells could not be reversed by treatment of the cells with proteasomal or lysosomal inhibitors. Eden et al. (2007) concluded that DAB2 is required in ARH fibroblasts to allow normal translation of LDL receptor mRNA.
By immunostaining, Yang et al. (2002) found Dab2 expression in the primitive endoderm of developing mice at embryonic day 4.5, immediately following implantation. Homozygous Dab2 deficiency was embryonic lethal before day 6.5 due to defective cell positioning and structure formation of the visceral endoderm. The absence of an organized visceral endoderm led to the growth failure of the inner cell mass.
Albertsen, H. M., Smith, S. A., Melis, R., Williams, B., Holik, P., Stevens, J., White, R. Sequence, genomic structure, and chromosomal assignment of human DOC-2. Genomics 33: 207-213, 1996. [PubMed: 8660969] [Full Text: https://doi.org/10.1006/geno.1996.0185]
Eden, E. R., Sun, X.-M., Patel, D. D., Soutar, A. K. Adaptor protein Disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia. Hum. Molec. Genet. 16: 2751-2759, 2007. [PubMed: 17761685] [Full Text: https://doi.org/10.1093/hmg/ddm232]
Hocevar, B. A., Smine, A., Xu, X.-X., Howe, P. H. The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway. EMBO J. 20: 2789-2801, 2001. [PubMed: 11387212] [Full Text: https://doi.org/10.1093/emboj/20.11.2789]
Inoue, A., Sato, O., Homma, K., Ikebe, M. DOC-2/DAB2 is the binding partner of myosin VI. Biochem. Biophys. Res. Commun. 292: 300-307, 2002. [PubMed: 11906161] [Full Text: https://doi.org/10.1006/bbrc.2002.6636]
Mok, S. C., Chan, W. Y., Wong, K. K., Cheung, K. K., Lau, C. C., Ng, S. W., Baldini, A., Colitti, C. V., Rock, C. O., Berkowitz, R. S. DOC-2, a candidate tumor suppressor gene in human epithelial ovarian cancer. Oncogene 16: 2381-2387, 1998. [PubMed: 9620555] [Full Text: https://doi.org/10.1038/sj.onc.1201769]
Mok, S. C., Wong, K.-K., Chan, R. K. W., Lau, C. C., Tsao, S.-W., Knapp, R. C., Berkowitz, R. S. Molecular cloning of differentially expressed genes in human epithelial ovarian cancer. Gynecol. Oncol. 52: 247-252, 1994. [PubMed: 8314147] [Full Text: https://doi.org/10.1006/gyno.1994.1040]
Rosenbauer, F., Kallies, A., Scheller, M., Knobeloch, K.-P., Rock, C. O., Schwieger, M., Stocking, C., Horak, I. Disabled-2 is transcriptionally regulated by ICSBP and augments macrophage spreading and adhesion. EMBO J. 21: 211-220, 2002. [PubMed: 11823414] [Full Text: https://doi.org/10.1093/emboj/21.3.211]
Sheng, Z., Smith, E. R., He, J., Tuppen, J. A., Martin, W. D., Dong, F. B., Xu, X.-X. Chromosomal location of murine Disabled-2 gene and structural comparison with its human ortholog. Gene 268: 31-39, 2001. [PubMed: 11368898] [Full Text: https://doi.org/10.1016/s0378-1119(01)00401-2]
Xu, X.-X., Yang, W., Jackowski, S., Rock, C. O. Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product. J. Biol. Chem. 270: 14184-14191, 1995. [PubMed: 7775479] [Full Text: https://doi.org/10.1074/jbc.270.23.14184]
Xu, X.-X., Yi, T., Tang, B., Lambeth, J. D. Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2. Oncogene 16: 1561-1569, 1998. [PubMed: 9569023] [Full Text: https://doi.org/10.1038/sj.onc.1201678]
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. Disabled-2 is essential for endodermal cell positioning and structure formation during mouse embryogenesis. Dev. Biol. 251: 27-44, 2002. [PubMed: 12413896] [Full Text: https://doi.org/10.1006/dbio.2002.0810]
Zhou, J., Scholes, J., Hsieh, J.-T. Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal prostatic epithelium and cancer. J. Biol. Chem. 278: 6936-6941, 2003. [PubMed: 12473651] [Full Text: https://doi.org/10.1074/jbc.M210628200]