Disease relevance of DAB2

• DOC-2/DAB2 is a potent tumor suppressor in many cancer types including prostate cancer [1].
• Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in breast cancer [2].
• Aberrant promoter methylation of human DAB2 interactive protein (hDAB2IP) gene in lung cancers [3].
• Expression microarray analysis identified a set of common differentially expressed genes, such as SPARC, DAB2 and VEGF, some of which have been shown implicated in ovarian cancer [4].
• Dramatically different expression levels of DOC-2/DAB2 mRNA and protein are observed among several human transitional cell carcinoma (TCC) cell lines, suggesting that transcriptional regulation may play a role in these cells [5].
• In univariable, but not in multivariable analysis, decreased DOC-2/DAB2 was associated with an increased probability of bladder cancer recurrence (log-rank test, P = 0.020) and bladder cancer-specific mortality (log-rank test, P = 0.023) [6].

High impact information on DAB2

• In vivo targeting and recruitment of myosin VI to clathrin-coated structures (CCSs) at the plasma membrane is mediated by Dab2 and PtdIns(4,5)P(2) binding [7].
• DOC2 proteins constitute a novel protein family that may function in secretion and contain a double C2 domain [8].
• These data suggest that DOC2 proteins are vesicular adapter proteins regulating munc18-syntaxin complexes and herewith synaptic vesicle docking [8].
• Dab2 could be conditionally deleted from the embryo without affecting normal development, showing that Dab2 is required in the visceral endoderm but dispensable in the embryo proper [9].
• Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport [9].

Biological context of DAB2

• Consistent with the effect on fibrinogen adhesion, Ser(24) phosphorylation of DAB2 was also involved in the negative regulation of alpha(IIb)beta(3)-induced T cell factor transcriptional activity [10].
• In K562 cells differentiating to the megakaryocytic lineage, down-regulation of DAB2 by DAB2 small interfering RNA augmented integrin alpha(IIb)beta(3) activation and resulted in an increase in cell adhesion to fibrinogen [10].
• DOC-2/DAB2, a novel phosphoprotein with signal-transducing capability, inhibits human prostatic cancer cells (Tseng, C.-P., Ely, B. D., Li, Y., Pong, R.-C., and Hsieh, J.-T. (1998) Endocrinology 139, 3542-3553) [11].
• In contrast, the S24A mutant acted like wild-type DAB2 and inhibited both beta-catenin- and plakoglobin-mediated T cell factor transactivation [10].
• The human DOC-2/DAB2 interactive protein gene (hDAB2IP) is a novel member of the Ras GTPase-activating gene family that is known to act as a tumor suppressor gene and is inactivated by methylation in prostate and breast cancers [3].

Anatomical context of DAB2

• Ectopic expression of DAB2 reversed the DAB2 small interfering RNA effect or, by itself, decreased fibrinogen adhesion of K562 cells [10].
• We investigate whether PDGF plays a role in the regulation of the adapter protein Disabled-2 (DAB2) that expresses abundantly in platelets and megakaryocytes [12].
• Differentially expressed in ovarian cancer-2/disabled 2 (DOC-2/DAB2) protein, often lost in prostate cancer and other cancer types, is a part of homeostatic machinery in normal prostate epithelium [13].
• Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton [14].
• Other stem cell markers, such as Oct 4, DAB2, and cMyc were also detected in normal human epidermal keratinocyte cultures [15].

Associations of DAB2 with chemical compounds

• In this study, the role of DAB2 in integrin alpha(IIb)beta(3)-mediated matrix protein fibrinogen adhesion and cell signaling was investigated [10].
• DAB2 induction and megakaryocytic differentiation was abrogated when cells were co-treated with the PDGF receptor inhibitor STI571 or when the conditioned medium was derived from TPA-plus STI571-treated cells [12].
• The secreted DAB2 binds to the extracellular region of alphaIIbbeta3 integrin on the platelet surface through the phosphotyrosine-binding domain [16].
• Biochemical and mutational analysis revealed that the DAB2 cell-adhesion Arg-Gly-Asp (RGD) motif (amino acid residues 64-66) and the alphaIIb-integrin-fibrinogen-binding region (amino acid residues 171-464) are important for the DAB2-platelet interactions [16].
• On the other hand, the differentiation agents DMSO and retinoic acid had no effect on DAB2 expression [17].

Physical interactions of DAB2

• The present findings suggest that myosin VI plays a role in transporting DOC-2/DAB2, a Ras cascade signaling molecule, thus involved in Ras signaling pathways [18].
• It appears that DOC-2/DAB2 can bind to Src homology 3 domain of c-Src and maintain it in an inactive conformation [1].

Enzymatic interactions of DAB2

• These findings reveal that Dab2 is differentially phosphorylated during the cell cycle by cdc2 and provide a potential feedback mechanism by which Dab2 inhibition of cell growth and proliferation may be regulated [19].

Regulatory relationships of DAB2

• Accordingly, transfection of an expression plasmid encoding secreted PDGF upregulated DAB2 [12].
• Myosin-VI is only recruited to clathrin-coated vesicles in cells that express high levels of Dab2, a clathrin-binding adapter protein [20].
• DOC-2/hDab-2 inhibits ILK activity and induces anoikis in breast cancer cells through an Akt-independent pathway [21].

Other interactions of DAB2

• We describe the cloning of DIP1/2, a novel gene that interacts with the N-terminal domain of DOC-2/DAB2 [22].
• Hence, DAB2 elicits distinct regulatory mechanisms in alpha(IIb)beta(3) and beta-catenin/plakoglobin signaling in a Ser(24) phosphorylation-dependent and -independent manner, respectively [10].
• Using a synthetic Ser(24) peptide (APS(24)KKEKKKGSEKTD) or recombinant DOC-2/DAB2 as substrates, PKCbetaII, PKCgamma, and PKCdelta (but not casein kinase II) directly phosphorylated Ser(24) in vitro [11].
• Given the divergence in the 3'UT region, the finding of the same exon 2 sequence at both the DAB1 and the DAB2 loci in one of the pheasant haplotypes also suggests that interlocus genetic exchange does occur [23].
• The C-terminal domain but not the N-terminal domain of DOC-2/DAB2 functions as a myosin VI anchoring site [18].

Analytical, diagnostic and therapeutic context of DAB2

• Through cellular localization and co-immunoprecipitation analysis, we demonstrate for the first time that Ser(24) phosphorylation promotes membrane translocation of DAB2 and its subsequent interaction with integrin beta(3), thereby defining a mechanism for DAB2 in regulating integrin alpha(IIb)beta(3) activation and inside-out signaling [10].
• Western blot analysis revealed that conditioned medium from 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated, megakaryocytic differentiating K562 cells upregulated DAB2 expression [12].
• We evaluated 24 normal and malignant bladder specimens for retinoid receptor, DAB2 and Midkine mRNA expression using RT-PCR [24].
• METHODS: DAB2 expression was analyzed by immunohistochemistry in 50 primary esophageal squamous cell carcinomas (ESCCs), 30 distinct hyperplasia, 15 dysplasia and 10 non-malignant esophageal tissues [25].
• To determine whether promoter hypermethylation contributes to loss of DAB2 expression in ESCCs, methylation status of DAB2 promoter was analyzed in DAB2 immuno-negative tumors using methylation-specific PCR [25].

References