Different statuses of the Wnt/Frizzled signaling cascade. (A) Wnt/Frizzled signaling is off when the Frizzled receptor is not engaged by a Wnt protein. Hence, the β-catenin degradation complex consisting of GSK-3β, Axin, APC and CK1 phosphorylates β-catenin at Ser/Thr residues, which ubiquitinates the latter and leads to degradation of it. As a result, β-catenin cannot enter the nucleus and activate transcription of target genes. (B) Upon binding of Wnt to the Frizzled receptor and co-localization of the LRP receptor, Dvl is activated, which disrupts the destruction complex. Now, β-catenin is accumulating in the cytoplasm and can enter the nucleus where it activates the TCF/LEF proteins and thereby activates the transcription of a broad range of genes. (C) Wnt proteins are prevented from binding to the Frizzled receptor by blockade of the cysteine-rich binding domains by UM206. In addition, the endogenous antagonist DKK prevents the LRP co-receptor from co-localization with the Frizzled receptor, thereby blocking the signaling transduction. sFRPs can scavenge Wnt proteins, which can reduce active Wnt signaling. Via all these mechanisms, β-catenin is prevented from entering the nucleus and transcription is not initiated.