Moreover, altered expression levels of TAK1 and RIPK3 in pulmonary endothelial cells of mice bearing primary tumors correlated with increased endothelial necroptosis and metastasis.
There was reduced expression of CHD1 in 8/21 and reduced MAP3K7 in 17/21 cases; 7/19 (37%) ERG-negative metastases had dual low expression of CHD1/MAP3K7.
Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both <i>in vitro</i> and <i>in vivo</i> The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells.
Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.
In this issue, Zhang et al.(2013) demonstrate that the ubiquitin ligase TRAF4 associates with the TGF-β receptors, rescuing them from degradation and ubiquitylating TAK1 to activate non-Smad signaling, which together promote metastasis of breast cancer cells.
Together, these findings suggest that TAK1 contributes to TGF-beta1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1-NF-kappaB-MMP-9 pathway.