Figure 7

Molecular genetic model (adapted from van Roy and Berx, 2008; Clevers and Nusse, 2012; Pei and Grishin, 2012; Van den Bossche et al, 2012). This in silico model is highly simplified and points out the crucial essentials of our results. (Top, left; canonical Wnt/β-catenin pathway) The destruction complex Axin1 leads to the phosphorylation of β-catenin. Phosphorylated β-catenin is ubiquitinated by the E3 ubiquitin ligase and then degraded proteasomally (off-status). The activation of the two receptors FZD and LRP5 by Wnt leads to membrane recruitment of the destruction complex. The E3 ubiquitin ligase is no longer able to ubiquitinate β-catenin of membrane-associated Axin1 (on-status). Consequently, the cytoplasmatic amount of β-catenin increases. MiR-23a and miR-24 lead to the downregulation of FZD5. Subsequently, Wnt cannot adhere to its receptors, the signal transduction is precluded and the Wnt/β-catenin signalling pathway remains in its off-status. In this case, the β-catenin phosphorylation, ubiquitination and degradation take place without any regulatory inhibition. The cytoplasmatic β-catenin amount decreases. Consequently, two inverse effects seem to occur. First, the lack of cytoplasmatic β-catenin could result in the destabilisation of catenation between the cadherin–catenin complex and the actin cytoskeleton. This could be responsible for the observed loss of cell polarity in the cell lines of group A. Second, an increase of cytoplasmatic β-catenin leads to an increase of nuclear β-catenin as well. βeta-catenin bound to TCF/LEF acts as a negative transcription factor (Jamora et al, 2003). It suppresses the expression of E-cadherin. Subsequently, the decrease of β-catenin leads to an increased expression of E-cadherin. This function of β-catenin seems to be a compensatory long-term feedback mechanism to maximise the small amount of cytoplasmatic β-catenin trying to restabilise the connection between the CCC and the cytoskeleton. (Bottom, right) Further, this attempt of compensatory feedback mechanism could be abrogated by the simultaneous downregulation of HNF1B. The expression of E-cadherin is enhanced by HNF1B serving as a positive transcription factor (Goomer et al, 1994). Thus, our results emphasise that the upregulation of miR-24 leads to the downregulation of HNF1B followed by decreased expression of E-sadherin with the loss of cell polarity. (Top, right; CCC) The cadherin–catenin complex (CCC) forms homologous cell–cell adhesion. The CCC includes the stable membrane-associated β-catenin pool. The E3 ubiquitin ligase leads to the ubiquitination of E-cadherin. Previous to the following endosomal degradation of E-cadherin, β-catenin dissociates from E-cadherin. Subsequently, the cytoplasmatic pool of β-catenin increases. We suppose that, most likely, TMEM92 interacts competitively with the E3 ubiquitin ligase and stabilises the amount of the CCC. MiR-24 leads to the downregulation of TMEM92. Downregulated TMEM92 fails to block the E3 ubiquitin ligase. Consequently, E-cadherin degradation is increased. The amount of E-cadherin decreases, cytoplasmatic β-catenin increases after dissociation, and the CCC and intercellular adhesion are destabilised. Possibly, the increase of dissociated β-catenin is immediately intercepted, because the same mechanism leads to a decreased pool of cytoplasmatic β-catenin. By competitive binding, TMEM92 inhibits the E3 ubiquitin ligase and consequently blocks β-catenin degradation. Thus, the gene silencing of TMEM92 by the upregulation of miR-24 appears to increase the degradation of β-catenin as well as E-cadherin. This mechanism also leads to the destabilisation of the CCC.