Regulatory role of DAB2 in MAPK, Wnt/β-catenin and canonical TGFβ pathways. In the absence of DAB2, TGFβ1/2/3 activate canonical signalling pathways through dimerisation of receptors TGFβRI and TGFβRII. This activates SMAD2 and enhances cell proliferation and EMT through expression of target genes. DAB2 PTB domain directly interacts with the MH2 domain of SMAD2/3, preventing its activation. DAB2 inhibits the canonical Wnt signalling pathway by preventing the interaction between Dvl and Axin, preventing destruction of the β-catenin destruction complex. In the absence of DAB2, Dvl and Axin interact separating the complex. β-catenin is then free to translocate to the nucleus where it promotes cell proliferation through expression of target c-myc and cyclin D1. DAB2 PRD interacts with the SH3 domains of SOS and c-Src in the MAPK pathway, inhibiting the signal transduction and in turn inhibiting cell proliferation and EMT.
TGFβ signalling is complex and can act as both a tumour suppressor and a tumour promoter. Loss of DAB2 expression in tumour compared to normal tissues is well documented (Table 1). A particular study in head and neck and vulval human squamous cell carcinoma (HSCC) suggested loss of DAB2 expression acts as a switch for TGFβ signalling to change from a tumour suppressor to a tumour promoter role . They found that with DAB2 expression, TGFβ activation of Smad2 and subsequent cell proliferation and motility were reduced. However, loss of DAB2 expression enhanced TGFβ Smad2 activation, reverting the effects on cell proliferation and enhanced cell motility . A study in EpH4 mammary epithelium overexpressing Ras cells (EpRas), suggested cross talk between MAPK and TGFβ signalling in promoting EMT and tumour metastasis . Another study in mammary epithelial cell lines (MCF10A1 and HME5-cdk4) demonstrated that DAB2 knockdown promoted activation of ERK which enhanced expression of TGFβ2 and promoted an EMT phenotype observed by reduced E-cadherin and enhanced N-cadherin and vimentin . Hocevar et al. suggests that the tumour suppressive effects of DAB2 may occur through dual inhibition of more than one key signalling pathway . In pancreatic cancer cell lines (COLO357 and PANC), DAB2 knock down enhanced TGFβ-mediated EMT through reduced E-cadherin and enhanced Snail, Slug and N-cadherin expression . A functional mechanism for DAB2 in maintaining an epithelial phenotype is through co-localisation with E-cadherin at the plasma membrane, maintaining apical junctions . Loss of DAB2 is associated with cytosolic localisation of E-cadherin and β-catenin . 2b1af7f3a8