DAB2 explained

Disabled homolog 2 is a protein that in humans is encoded by the DAB2 gene.^{[1] [2]}

Function

DAB2 mRNA is expressed in normal ovarian epithelial cells but is down-regulated or absent from ovarian carcinoma cell lines. 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 down-regulation of DAB2 may play an important role in ovarian carcinogenesis. This gene was initially named DOC2 (for Differentially expressed in Ovarian Cancer) and is distinct from the DOC2A and DOC2B genes (for double C2-like domains, alpha and beta).^[3]

Interactions

DAB2 has been shown to interact with:

• C-src tyrosine kinase,^[4]
• Cdk1,^[5]
• DAB2IP,^[6]
• DVL2,
• DVL3,^[7]
• LRP2,^[8]
• MYO6,^{[9] [10]}
• Mothers against decapentaplegic homolog 2,
• Mothers against decapentaplegic homolog 3^[11]
• PIN1,^[5] and
• Src.^[4]

Further reading

• 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. . 52 . 2 . 247–52 . 1994 . 8314147 . 10.1006/gyno.1994.1040 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Res. . 6 . 9 . 791–806 . 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Xu XX, Yi T, Tang B, Lambeth JD . Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2 . Oncogene . 16 . 12 . 1561–9 . 1998 . 9569023 . 10.1038/sj.onc.1201678 . free .
• Fazili Z, Sun W, Mittelstaedt S, Cohen C, Xu XX . Disabled-2 inactivation is an early step in ovarian tumorigenicity . Oncogene . 18 . 20 . 3104–13 . 1999 . 10340382 . 10.1038/sj.onc.1202649 . free .
• Tseng CP, Ely BD, Pong RC, Wang Z, Zhou J, Hsieh JT . The role of DOC-2/DAB2 protein phosphorylation in the inhibition of AP-1 activity. An underlying mechanism of its tumor-suppressive function in prostate cancer . J. Biol. Chem. . 274 . 45 . 31981–6 . 1999 . 10542228 . 10.1074/jbc.274.45.31981 . free .
• Oleinikov AV, Zhao J, Makker SP . Cytosolic adaptor protein Dab2 is an intracellular ligand of endocytic receptor gp600/megalin . Biochem. J. . 347 Pt 3 . 3 . 613–21 . 2000 . 10769163 . 1220996 . 10.1042/0264-6021:3470613 .
• Sheng Z, Sun W, Smith E, Cohen C, Sheng Z, Xu XX . Restoration of positioning control following Disabled-2 expression in ovarian and breast tumor cells . Oncogene . 19 . 42 . 4847–54 . 2000 . 11039902 . 10.1038/sj.onc.1203853 . free .
• Sheng Z, He J, Tuppen JA, Sun W, Fazili Z, Smith ER, Dong FB, Xu XX . Structure, sequence, and promoter analysis of human disabled-2 gene (DAB2) . Genomics . 70 . 3 . 381–6 . 2000 . 11161789 . 10.1006/geno.2000.6383 .
• Morris SM, Cooper JA . Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2 . Traffic . 2 . 2 . 111–23 . 2001 . 11247302 . 10.1034/j.1600-0854.2001.020206.x . 33186168 . free .
• Zhou J, Hsieh JT . The inhibitory role of DOC-2/DAB2 in growth factor receptor-mediated signal cascade. DOC-2/DAB2-mediated inhibition of ERK phosphorylation via binding to Grb2 . J. Biol. Chem. . 276 . 30 . 27793–8 . 2001 . 11371563 . 10.1074/jbc.M102803200 . free .
• 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. . 20 . 11 . 2789–801 . 2001 . 11387212 . 125498 . 10.1093/emboj/20.11.2789 .
• Wang Z, Tseng CP, Pong RC, Chen H, McConnell JD, Navone N, Hsieh JT . The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2 . J. Biol. Chem. . 277 . 15 . 12622–31 . 2002 . 11812785 . 10.1074/jbc.M110568200 . free .
• Inoue A, Sato O, Homma K, Ikebe M . DOC-2/DAB2 is the binding partner of myosin VI . Biochem. Biophys. Res. Commun. . 292 . 2 . 300–7 . 2002 . 11906161 . 10.1006/bbrc.2002.6636 .
• 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. . 21 . 18 . 4915–26 . 2002 . 12234931 . 126284 . 10.1093/emboj/cdf487 .
• Morris SM, Tallquist MD, Rock CO, Cooper JA . Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport . EMBO J. . 21 . 7 . 1555–64 . 2002 . 11927540 . 125955 . 10.1093/emboj/21.7.1555 .
• 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 . 3 . 5 . 331–41 . 2002 . 11967127 . 10.1034/j.1600-0854.2002.30503.x . 25079713 .
• Zhou J, Scholes J, Hsieh JT . Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal prostatic epithelium and cancer . J. Biol. Chem. . 278 . 9 . 6936–41 . 2003 . 12473651 . 10.1074/jbc.M210628200 . free .
• Calderwood DA, Fujioka Y, de Pereda JM, García-Alvarez B, Nakamoto T, Margolis B, McGlade CJ, Liddington RC, Ginsberg MH . Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling . Proc. Natl. Acad. Sci. U.S.A. . 100 . 5 . 2272–7 . 2003 . 12606711 . 151330 . 10.1073/pnas.262791999 . 2003PNAS..100.2272C . free .

Notes and References

1. 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 . 33 . 2 . 207–13 . January 1997 . 8660969 . 10.1006/geno.1996.0185 .
2. 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 . 16 . 18 . 2381–7 . June 1998 . 9620555 . 10.1038/sj.onc.1201769 . free .
3. Web site: Entrez Gene: DAB2 disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila).
4. Zhou J, Scholes J, Hsieh JT . Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal prostatic epithelium and cancer . J. Biol. Chem. . 278 . 9 . 6936–41 . February 2003 . 12473651 . 10.1074/jbc.M210628200 . free .
5. He J, Xu J, Xu XX, Hall RA . Cell cycle-dependent phosphorylation of Disabled-2 by cdc2 . Oncogene . 22 . 29 . 4524–30 . July 2003 . 12881709 . 10.1038/sj.onc.1206767 . free .
6. Wang Z, Tseng CP, Pong RC, Chen H, McConnell JD, Navone N, Hsieh JT . The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2 . J. Biol. Chem. . 277 . 15 . 12622–31 . April 2002 . 11812785 . 10.1074/jbc.M110568200 . free .
7. Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH . Regulation of the Wnt signaling pathway by disabled-2 (Dab2) . EMBO J. . 22 . 12 . 3084–94 . June 2003 . 12805222 . 162138 . 10.1093/emboj/cdg286 .
8. Oleinikov AV, Zhao J, Makker SP . Cytosolic adaptor protein Dab2 is an intracellular ligand of endocytic receptor gp600/megalin . Biochem. J. . 347 Pt 3 . 3. 613–21 . May 2000 . 10769163 . 1220996 . 10.1042/0264-6021:3470613.
9. 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 . 3 . 5 . 331–41 . May 2002 . 11967127 . 10.1034/j.1600-0854.2002.30503.x. 25079713 .
10. Inoue A, Sato O, Homma K, Ikebe M . DOC-2/DAB2 is the binding partner of myosin VI . Biochem. Biophys. Res. Commun. . 292 . 2 . 300–7 . March 2002 . 11906161 . 10.1006/bbrc.2002.6636 .
11. 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. . 20 . 11 . 2789–801 . June 2001 . 11387212 . 125498 . 10.1093/emboj/20.11.2789 .