Trends in Cell Biology
Volume 26, Issue 12, December 2016, Pages 956-967
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Review
β-Catenin-Independent Roles of Wnt/LRP6 Signaling

https://doi.org/10.1016/j.tcb.2016.07.009Get rights and content

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Wnt/LRP6 signaling is thought to proceed by β-catenin mediated transcription. However, this pathway branches off to trigger a variety of other processes, revising the traditional transcription-centric view.

Wnt/STOP signaling is one such novel branch of Wnt/LRP6 signaling, which peaks during mitosis to slow down protein degradation as cells prepare to divide.

Transcription-independent Wnt/LRP6 signaling regulates cell growth and mitotic progression in dividing cells, axonal remodeling in post-mitotic neurons, and maturation of germ cells.

Wnt/LRP6 signaling is best known for the β-catenin-dependent regulation of target genes. However, pathway branches have recently emerged, including Wnt/STOP signaling, which act independently of β-catenin and transcription. We review here the molecular mechanisms underlying β-catenin-independent Wnt/LRP6 signaling cascades and their implications for cell biology, development, and physiology.

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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