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Wnt Pathway | Overview

About WNT - Overview

What happens when the Wnt signaling pathway is DOWNREGULATED?

In the absence of Wnt ligands, the pathway remains inactive, with relatively low levels of Wnt target gene expression.5

  • In the inactive state, β-catenin destruction complex—composed of the tumor suppressor protein APC, the scaffolding protein Axin, and the protein kinases CK1 and GSK3—continuously phosphorylates β-catenin, ultimately marking it for proteasomal degradation5,6
  • A transcriptional corepressor called Groucho binds to DNA-binding proteins in the TCF/LEF family and represses transcriptional activation5,6
  • Disrupting the homeostasis of the Wnt signaling pathway can lead to multiple disease pathologies—for example, the loss of function in LRP5 or LRP6, key components of the Wnt signaling pathway, can contribute to high bone mass2
Inactive Wnt Pathway

What happens when the Wnt signaling pathway is ACTIVATED?

In the presence of Wnt ligands, activation of the Wnt signaling pathway increases free β-catenin and stimulates transcription of Wnt target genes.5,6

  • Activation starts when Wnt proteins bind to a Frizzled (FZD) family protein and either LRP5 or LRP6 co-receptors on the cell surface, setting off the signaling cascade5,6
  • The axin-binding protein Dishevelled binds to Axin, inactivating the β-catenin destruction complex, resulting in the accumulation of β-catenin in the cytoplasm. β-catenin then translocates to the nucleus5
  • In the nucleus, β-catenin interacts with DNA-binding proteins in the TCF/LEF family to activate Wnt target genes, which play multiple roles in developmental processes and tissue homeostasis1,5,6
  • In multiple types of cancer, the overactivation of the Wnt signaling pathway due to mutations may contribute to the initiation of tumorigenesis. For example, mutations to APC—a negative regulator of β-catenin—can contribute to colon cancer3,4
Activation by Wnt

The NON-canonical Wnt pathways

There are 2 primary non-canonical, β-catenin–independent Wnt signaling pathways that may play a part in both transcriptional and non-transcriptional cellular responses.7

 

The CA2+ Pathway7

  • Activates a different cascade starting with FZD receptors, triggering Ca2+ release from intracellular stores through activated phospholipase C
  • Results in the transcription of genes that control cell fate and migration, and is implicated in cancer, inflammation, and neurodegeneration

The Planar Cell Polarity Pathway7

  • Activates a cascade starting with FZD receptors that affects rearrangement in the cytoskeleton and gene expression
  • Regulates cell polarity in morphogenetic processes, including gastrulation, neural tube closure, and stereocilia orientation in the inner ear

The canonical and non-canonical Wnt signaling pathways interact with each other and other pathways1,8-11

The canonical and non-canonical Wnt signaling pathways interact with multiple pathways, including the NF-κB, MAPK, and JNK pathways.8,9

  • Canonical Wnt signaling and NF-κB cross-regulation are responsible for cellular and tissue homeostasis in multiple cell and tissue types8
  • The positive regulation of the canonical Wnt signaling pathway by the NF-κB pathway may play a role in cancer development8
  • The cross-talk among the non-canonical Wnt, MAPK, and JNK pathways has been shown to impact osteoblast differentiation9

The Wnt signaling pathways also interact with the TGF-β and BMP pathways.10,11

  • During embryonic development, these interactions are important for stem cell maintenance, body patterning, and cell fate determination10
  • Communication among these pathways has been demonstrated within the nucleus, where they synergistically regulate multiple shared target genes10
  • In intervertebral discs, this cross-talk is important for proteoglycan synthesis, the loss of which is responsible for disc degeneration11

The canonical and non-canonical Wnt signaling pathways also interact and coordinate with each other to regulate processes such as embryonic development, stem cell maintenance, tissue homeostasis, and wound healing. And when aberrantly regulated, these pathways can be involved in tumorigenesis and metastasis, as well as contribute to other diseases.1

 

Regulation of the Wnt signaling pathway is a finely tuned balancing act aimed toward cellular differentiation and the maintenance of tissue homeostasis8,12

 

Abbreviations: APC, adenomatous polyposis coli; BMP, bone morphogenetic protein; CK1, casein kinase 1; GSK3, glycogen synthase kinase 3; JNK, c-Jun N-terminal kinase; LEF, lymphoid enhancer–binding factor; LRP, lipoprotein receptor–related protein; MAPK, mitogen-activated protein kinase; TCF, T-cell factor; TGF-β, transforming growth factor β.

References: 1. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13(7):513-532. 2. Semenov MV, He X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J Biol Chem. 2006;281(50):38276-38284. 3. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13(1):11-26. 4. Haegebarth A, Clevers H. Wnt signaling, Lgr5, and stem cells in the intestine and skin. Am J Pathol. 2009;174(3):715-721. 5. Nusse R. Wnt signaling in disease and in development. Cell Res. 2005;15(1):28-32. 6. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843-850. 7. Gómez-Orte E, Sáenz-Narciso B, Moreno S, Cabello J. Multiple functions of the noncanonical Wnt pathway. Trends Genet. 2013;29(9):545-553. 8. Ma B, Hottiger MO. Crosstalk between Wnt/β-catenin and NF-κB signaling pathway during inflammation. Front Immunol. 2016;7:378. doi:10.3389/fimmu.2016.00378. 9. Zhang Y, Pizzute T, Pei M. A review of crosstalk between MAPK and Wnt signals and its impact on cartilage regeneration. Cell Tissue Res. 2014;358(3):633-649. 10. Guo X, Wang XF. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res. 2009;19(1):71-88. 11. Hiyama A, Sakai D, Tanaka M, et al. The relationship between the Wnt/β-catenin and TGF-β/BMP signals in the intervertebral disc cell. J Cell Physiol. 2011;226(5):1139-1148. 12. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469-480.