Regulation of MT1-MMP activity by β-catenin in MDCK non-cancer and HT1080 cancer cells.

Past studies on β-catenin in cancer cells focused on nuclear localized β-catenin and its involvement in the Wnt pathway. Our goal here was to investigate the function of β-catenin in both the cytoplasm and nucleus on the regulation of MT1-MMP expression and activity. We found that β-catenin in MDCK non-cancer cells inhibited the cell surface localization of MT1-MMP, and thus its proteolytic activity on pro-MMP2 activation, via direct interaction with the 18-amino-acid cytoplasmic tail of MT1-MMP in the cytoplasm. In contrast, β-catenin in HT1080 cancer cells enhanced the activity of MT1-MMP by entering the nucleus and activating transcription factor Tcf-4/Lef, and elevating the level of MT1-MMP protein. We also found that enhancement of cell growth in three-dimensional (3-D)/two-dimensional (2-D) type I collagen gels and of cell migration by MT1-MMP were inhibited by β-catenin in MDCK cells, whereas these functions were enhanced in HT1080 cells. In addition, regulation of MT1-MMP by β-catenin involved E-cadherin in MDCK cells and Wnt-3a in HT1080 cells. Taken together, our results present a differential effect of cytoplasmic and nuclear β-catenin on MT1-MMP activity in non-cancer cells versus cancer cells. These differences were most probably due to different subcellular locations and different involved pathways of β-catenin in these cells.

Liu P ，Yang J ，Pei J ，Pei D ，Wilson MJ ... -  《-》

N-glycosylation gene DPAGT1 is a target of the Wnt/beta-catenin signaling pathway.

Sengupta PK ，Bouchie MP ，Kukuruzinska MA 《-》

Gonadotropin-releasing hormone-II increases membrane type I metalloproteinase production via beta-catenin signaling in ovarian cancer cells.

Ling Poon S ，Lau MT ，Hammond GL ，Leung PC ... -  《-》

Phospholipase D1 drives a positive feedback loop to reinforce the Wnt/beta-catenin/TCF signaling axis.

Activation of the Wnt signaling pathway occurs frequently in human cancers, but an understanding of the targets and regulation of this important pathway remains incomplete. In this study, we report that phospholipase D (PLD), a cell survival mediator that is upregulated in cancer, is an important target of the Wnt signaling pathway that functions in a positive feedback loop to reinforce pathway output. PLD1 expression and activity was enhanced by treatment with Wnt3a and glycogen synthase kinase-3 inhibitors, and the Wnt pathway-regulated transcription factors beta-catenin and TCF-4 were required for this effect. Three functional TCF-4-binding sites were identified within the PLD1 promoter. Interestingly, suppressing PLD1 blocked the ability of beta-catenin to transcriptionally activate PLD1 and other Wnt target genes by preventing beta-catenin/TCF-4 complex formation. Conversely, tactics to elevate intracellular levels of phosphatidic acid, the product of PLD1 enzyme activity, enhanced beta-catenin/TCF-4 complex formation as well as beta-catenin-dependent TCF transcriptional activity. In cell-based assays, PLD1 was necessary for the anchorage-independent growth driven by Wnt/beta-catenin signaling, whereas beta-catenin/TCF-4 was necessary for the anchorage-independent growth driven by PLD1 activation. Taken together, our findings define a function for PLD1 in a positive feedback loop of Wnt/beta-catenin/TCF-4 signaling that provides new mechanistic insights into cancer, with implications of novel strategies to disrupt Wnt signaling in cancer.

Kang DW ，Lee SH ，Yoon JW ，Park WS ，Choi KY ，Min do S ... -  《-》

Human telomerase reverse transcriptase (hTERT) is a novel target of the Wnt/β-catenin pathway in human cancer.

Zhang Y ，Toh L ，Lau P ，Wang X ... -  《-》