Although the mechanism of Wnt signal transduction described thus far may seem complicated enough, additional players continue to be identified. For example, protein phosphatase 2A appears to play a role in regulating ft-catenin stability although it is unclear whether it promotes ft-catenin degradation or stabilization. The Droso-phila naked cuticle gene has recently been shown to be a novel cytoplasmic antagonist that may limit the potency, duration or distribution of Wnt signals. Recent evidence also implicates components of the mitogen-activated protein kinase (MAPK) pathway, transforming growth factor-ft-activated kinase (TAK-1) andNEMO-like kinase (NLK) as regulators of Wnt signalling. However, it remains to be determined whether these genes are true components of the Wnt pathway or whether they act in parallel to the canonical Wnt pathway.
In addition to these players, it has become clear that cross-talk between the Wnt pathway and the Transforming
Growth Factor ft (TGF-ft) signalling pathway plays an important role in regulating Wnt/ft-catenin signalling both during development and in human disease. For example, the secreted Wnt antagonist Cerberus can also interact with members of the BMP and Nodal families of TGF-ft-like signalling molecules, suggesting that Cerberus can function as a multivalent modulator of both Wnt and TGF-ft/ BMP signalling. In addition, Wnt and TGF-ft signalling pathways also cross-talk inside the cell. Several recent papers have shown that TCF/LEF transcription factors interact with members of the SMAD family of TGF-ft/ BMP signal mediators. Specifically, Lef-1 can form complexes with three different SMAD proteins: SMAD-2 and -3, effectors for TGF-ft and Activin signals; and SMAD-4, a ubiquitous effector for all TGF-ft/BMP signalling pathways. Through these interactions, SMAD proteins were found to stimulate synergistically transcription of specific Wnt target genes. These data are intriguing since mutations in components of both the Wnt (APC and ft-catenin) and TGF-ft signalling pathways (TGF-ft receptor type II, SMAD-2, -3 and -4) are associated with colorectal cancers. Furthermore, mice double heterozygous for both APC and SMAD-4 display intestinal polyps that develop into more malignant tumours than those in mice heterozygous for APC alone (Takaku et al., 1998). Together these data argue that the Wnt and TGF-ft pathways cross-talk to regulate cooperatively gene expression and that this synergistic interaction may be important both during development and in cancer.
ft-Catenin levels can also be regulated by Wnt-independent mechanisms. For example, expression of integrin-linked kinase in mammalian cells promotes the stabilization and nuclear accumulation of ft-catenin (Novak et al., 1998). Presenilin proteins have also been implicated as regulators of ft-catenin stability. Mutations in presenilin associated with the rapid onset of Alzheimer disease decrease the stability of ft-catenin in neurons. This effect on ft-catenin was also correlated with an increase in the susceptibility of neurons to apoptosis resulting from the accumulation of ft-amyloid protein. Given the ability of these signalling pathways to modulate ft-catenin stability, it seems likely that ft-catenin may regulate many cellular processes independent of its role in Wnt signalling.
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