Trends in Cell Biology
Reviewβ-Catenin-Independent Roles of Wnt/LRP6 Signaling
Section snippets
Wnt/LRP6 Signaling
Wnt proteins are secreted short-range signals found in all metazoans, which function in embryonic development and adult tissue homeostasis by regulating fate, proliferation, polarity, and migration of cells 1, 2, 3. Misregulation of Wnt signaling can lead to disease, notably cancer 4, 5. In most mammals there are 19 Wnt genes that can signal through a variety of receptors and downstream pathways (reviewed in [6]). Roughly, Wnt signaling is subdivided into a canonical pathway, also known as the
The Upstream Cascade
Upon Wnt ligand binding, Fzd/LRP6 receptors cluster together with the scaffold protein Dishevelled (Dvl) into signalosomes, which are endocytosed 10, 11, 12 (Figure 1B). Signalosome formation induces LRP6 phosphorylation by glycogen synthase kinase 3 (GSK3) at PPPSP motifs, which primes adjacent S/T clusters for phosphorylation by casein kinase 1γ (CK1γ) 13, 14.
In addition to GSK3, other kinases phosphorylate the LRP6 PPPSP motifs in a Wnt-independent manner (reviewed in [15]). For instance,
Wnt/β-Catenin Signaling
At the heart of canonical Wnt signaling is the transcriptional regulator β-catenin which, in the absence of Wnt ligands, is targeted for proteasomal degradation [21]. Wnt/LRP6 signaling inhibits GSK3, which allows newly synthesized β-catenin to accumulate in the cytoplasm and translocate to the nucleus where it binds members of the T cell factor/lymphocyte enhancer factor family (TCF/LEF) to initiate transcription of target genes 21, 30, 31. The transcriptional program regulated by
Wnt-Dependent Stabilization of Proteins (Wnt/STOP)
GSK3 is a promiscuous kinase that phosphorylates many other proteins in addition to β-catenin [36]. Phosphorylation by GSK3 can generate phospho-degrons that are recognized by dedicated E3 ubiquitin ligases, notably β-TrCP, FBXW7, and NEDD4L, which target these substrates for proteasomal degradation 36, 37, 38, 39, 40. Wnt/LRP6 signaling can sequester up to 70% of cellular GSK3 activity in multivesicular bodies, as well as a large proportion of the cellular ubiquitin pool, thereby stabilizing
Other β-Catenin-Independent Cascades of Wnt/LRP6 Signaling
In addition to Wnt/STOP, other β-catenin-independent Wnt/LRP6 signaling cascades branch off at GSK3, which not only targets proteins to degradation but can also modulate their activity by phosphorylation. GSK3 inhibition by Wnt/LRP6 signaling activates target of rapamycin (TOR) to increase protein translation [43], modulates the activity of microtubule-associated proteins (reviewed in [44]), and inhibits the activity of protein phosphatase 1 (PP1) [18]. Wnt/LRP6 signaling also regulates
Cell Growth
Cells need to synchronize cell-cycle progression with cell growth to maintain a constant cell size along their lineages. To achieve this, mitogenic pathways such as Wnt/LRP6 signaling coregulate anabolic/catabolic cascades and cell-cycle effectors to maintain proliferation [48]. GSK3 is a key regulator of cellular catabolism, and inhibits cell growth by blocking glucose intake, reduces TOR-mediated protein translation, and destabilizes key cell-cycle effectors 49, 50, 51. Thus, by inhibiting
Crosstalk with other Signaling Cascades
Cells typically receive multiple signals, and particular components act as signaling hubs that coordinate crosstalk between cascades. GSK3 is a key example of a signaling hub which not only integrates several inputs, such as Wnt, EGF, and insulin, but also multiple outputs (e.g., Table 1), thereby allowing Wnt/LRP6 signaling to directly regulate other pathways independently of β-catenin.
During vertebrate axial patterning, the dorsal–ventral and anterior–posterior axes are regulated by BMP and
Concluding Remarks and Future Directions
The discovery of β-catenin-independent Wnt/LRP6 signaling branches raises the important question of the extent to which Wnt responses are mediated by transcriptional or β-catenin-independent routes (see Outstanding Questions). At the one extreme, during mouse gastrulation and Drosophila segmentation, Wnt3/Wg mutants phenocopy β-catenin/armadillo mutants, suggesting that transcriptional regulation is the dominant signaling mode 85, 86, 87. At the other extreme, in transcriptionally-silent mouse
Acknowledgments
We apologize to all authors whose primary work could not be cited owing to space constraints or whose work was inadvertently overlooked. This work was supported by the Deutsche Forschungsgemeinschaft.
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