Fig. 9.

Model depicting the proposed mechanism of DKK3-mediated regulation of YAP/TAZ and β-catenin in CAFs. On CAFs, DKK3 destabilises Wnt negative regulator Kremen leading to increased LRP6 membrane localisation, which in turn stabilises YAP/TAZ and β-catenin levels via canonical Wnt. Whereas β-catenin signalling is dispensable for CAFs to remodel the ECM and promote cancer cell growth and invasion, DKK3-driven YAP activation is required to induce a tumour-promoting phenotype. Absence of DKK3 in DKK3-null CAFs and NFs is associated with decreased YAP/TAZ and β-catenin activity. In CAFs, loss of DKK3 leads to concomitant upregulation of Kremen, LRP6 inactivation and YAP/TAZ and β-catenin destabilization. In this scenario, depletion of Kremen1/2 is able to rescue LRP6 membrane localisation and YAP/TAZ and β-catenin activity