The scaffold protein disabled 2 (DAB2) and its role in tumor development and progression.

BACKGROUND: Disabled 2 (DAB2) is a multifunctional protein that has emerged as a critical component in the regulation of tumor growth. Its dysregulation is implicated in various types of cancer, underscoring its importance in understanding the molecular mechanisms underlying tumor development and progression. This review aims to unravel the intricate molecular mechanisms by which DAB2 exerts its tumor-suppressive functions within cancer signaling pathways. METHODS AND RESULTS: We conducted a comprehensive review of the literature focusing on the structure, expression, physiological functions, and tumor-suppressive roles of DAB2. We provide an overview of the structure, expression, and physiological functions of DAB2. Evidence supporting DAB2's role as a tumor suppressor is explored, highlighting its ability to inhibit cell proliferation, induce apoptosis, and modulate key signaling pathways involved in tumor suppression. The interaction between DAB2 and key oncogenes is examined, elucidating the interplay between DAB2 and oncogenic signaling pathways. We discuss the molecular mechanisms underlying DAB2-mediated tumor suppression, including its involvement in DNA damage response and repair, regulation of cell cycle progression and senescence, and modulation of epithelial-mesenchymal transition (EMT). The review explores the regulatory networks involving DAB2, covering post-translational modifications, interactions with other tumor suppressors, and integration within complex signaling networks. We also highlight the prognostic significance of DAB2 and its role in pre-clinical studies of tumor suppression. CONCLUSION: This review provides a comprehensive understanding of the molecular mechanisms by which DAB2 exerts its tumor-suppressive functions. It emphasizes the significance of DAB2 in cancer signaling pathways and its potential as a target for future therapeutic interventions.

AMPK-upregulated microRNA-708 plays as a suppressor of cellular senescence and aging via downregulating disabled-2 and mTORC1 activation.

Senescence-associated microRNAs (SA-miRNAs) are important molecules for aging regulation. While many aging-promoting SA-miRNAs have been identified, confirmed aging-suppressive SA-miRNAs are rare, that impeded our full understanding on aging regulation. In this study, we verified that miR-708 expression is decreased in senescent cells and aged tissues and revealed that miR-708 overexpression can alleviate cellular senescence and aging performance. About the molecular cascade carrying the aging suppressive action of miR-708, we unraveled that miR-708 directly targets the 3'UTR of the disabled 2 (Dab2) gene and inhibits the expression of DAB2. Interestingly, miR-708-caused DAB2 downregulation blocks the aberrant mammalian target of rapamycin complex 1 (mTORC1) activation, a driving metabolic event for senescence progression, and restores the impaired autophagy, a downstream event of aberrant mTORC1 activation. We also found that AMP-activated protein kinase (AMPK) activation can upregulate miR-708 via the elevation of DICER expression, and miR-708 inhibitor is able to blunt the antiaging effect of AMPK. In summary, this study characterized miR-708 as an aging-suppressive SA-miRNA for the first time and uncovered a new signaling cascade, in which miR-708 links the DAB2/mTOR axis and AMPK/DICER axis together. These findings not only demonstrate the potential role of miR-708 in aging regulation, but also expand the signaling network connecting AMPK and mTORC1.

Genetic polymorphism of the Dab2 gene and its association with Type 2 Diabetes Mellitus in the Chinese Uyghur population.

Objective: The human Disabled-2 (Dab2) protein is an endocytic adaptor protein, which plays an essential role in endocytosis of transmembrane cargo, including low-density lipoprotein cholesterol (LDL-C). As a candidate gene for dyslipidemia, Dab2 is also involved in the development of type 2 diabetes mellitus(T2DM). The aim of this study was to investigate the effects of genetic variants of the Dab2 gene on the related risk of T2DM in the Uygur and Han populations of Xinjiang, China. Methods: A total of 2,157 age- and sex-matched individuals (528 T2DM patients and 1,629 controls) were included in this case-control study. Four high frequency SNPs (rs1050903, rs2255280, rs2855512 and rs11959928) of the Dab2 gene were genotyped using an improved multiplex ligation detection reaction (iMLDR) genotyping assay, and the forecast value of the SNP for T2DM was assessed by statistical analysis of clinical data profiles and gene frequencies. Results: We found that in the Uygur population studied, for both rs2255280 and rs2855512, there were significant differences in the distribution of genotypes (AA/CA/CC), and the recessive model (CC vs. CA + AA) between T2DM patients and the controls (P < 0.05). After adjusting for confounders, the recessive model (CC vs. CA + AA) of both rs2255280 and rs2855512 remained significantly associated with T2DM in this population (rs2255280: OR = 5.303, 95% CI [1.236 to -22.755], P = 0.025; rs2855512: OR = 4.892, 95% CI [1.136 to -21.013], P = 0.033). The genotypes (AA/CA/CC) and recessive models (CC vs. CA + AA) of rs2855512 and rs2255280 were also associated with the plasma glucose and HbA1c levels (all P < 0.05) in this population. There were no significant differences in genotypes, all genetic models, or allele frequencies between the T2DM and control group in the Han population group (all P > 0.05). Conclusions: The present study suggests that the variation of the Dab2 gene loci rs2255280 and rs2855512 is related to the incidence of T2DM in the Uygur population, but not in the Han population. In this study, these variations in Dab2 were an independent predictor for T2DM in the Uygur population of Xinjiang, China.

DAB2 suppresses gastric cancer migration by regulating the Wnt/ß-catenin and Hippo-YAP signaling pathways.

BACKGROUND: Disabled-2 (DAB2), a potential tumor suppressor, plays an in important role in cancer development and cellular differentiation. Its lower expression levels have founded in many cancers. In addition, DAB2 is involved in multiple signaling pathways, including TGF-ß and Wnt signal pathways. Gastric cancer (GC) is a common gastrointestinal malignant tumor. Nonetheless, the role of DAB2 in GC remains unclear. METHODS: Thirty-seven clinical specimens of GC tissues and adjacent non-tumor tissues were examined by immunohistochemistry. Proteins were extracted from two of them to perform Western blot analysis. Then, CMV-MCS-3FLAG-SV40-DAB2 and si-DAB2 were transfected into MGC and SGC cell line, respectively. The migration of GC cells was evaluated by transwell migration assay. And, the expression of migration related proteins was detected by Western blot and immunofluorescence (IF). RESULTS: Eighty-six percent (32/37) of patients DAB2 staining was reduced in GC tissues compared to adjacent normal tissues. Further studies showed that in six human GC cell lines, the level of DAB2 expression was lower than normal gastric epithelial cells, and that DAB2 was closely related to cell migration in vitro. In DAB2 silenced cells, the Wnt/ß-catenin signaling was increased and the Hippo-YAP pathway was affected. In addition, lower DAB2 level led to nuclear translocation of ß-catenin and Yap. CONCLUSIONS: The lower expression of DAB2 regulates cell migration in GC via interfering with the Wnt and Hippo signaling pathway. Our findings suggested that DAB2 played an important role in the migration of GC.