WNT and β-catenin signalling: diseases and therapies

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Abstract

WNT signalling has been studied primarily in developing embryos, in which cells respond to WNTs in a context-dependent manner through changes in survival and proliferation, cell fate and movement. But WNTs also have important functions in adults, and aberrant signalling by WNT pathways is linked to a range of diseases, most notably cancer. What is the full range of diseases that involve WNT pathways? Can inhibition of WNT signalling form the basis of an effective therapy for some cancers? Could activation of WNT signalling provide new therapies for other clinical conditions? Finally, on the basis of recent experiments, might WNTs normally participate in self-renewal, proliferation or differentiation of stem cells? If so, altering WNT signalling might be beneficial to the use of stem cells for therapeutic means.

Key Points

  • WNTs are secreted ligands that activate at least two signalling pathways in vertebrates.

  • Altered function or levels of components of the WNT/β-catenin pathway are associated with proliferative diseases including cancer, as well as Alzheimer disease, osteoarthritis, tooth development, and diseases of the bone, eye and heart.

  • Altered function of the WNT/calcium pathway is implicated as a tumour-suppressor pathway, and as a regulator of cancer metastasis.

  • Both activators and inhibitors of WNT pathways are being developed as candidate therapeutic agents.

  • Manipulation of WNT signalling might be important in the development of therapies that are based on human stem cells.

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Figure 1: WNT/β-catenin signalling.
Figure 2: WNT/calcium signalling.
Figure 3: Therapeutic targets in WNT/β-catenin signalling.

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Acknowledgements

R.T.M. is supported as an investigator and A.K. as an associate of the Howard Hughes Medical Institute, to which we are indebted for support. We thank M. Kahn and P. Yaworsky for reviewing a draft of this manuscript. We acknowledge funding by the Alzheimer's Association and by the National Institutes of Health. G.V.D. is funded by the Pew Latin American Fellows Program in the Biomedical Sciences, and A.D.K. is funded by the National Institutes of Health. As with any review, this one is a snapshot that is blurred by the fast pace of advancement in the field. We therefore apologize for any omissions or oversights.

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Correspondence to Randall T. Moon.

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DATABASES

Entrez

APC

ILK

Lef1

LRP5

LRP6

p53

PKD1

Tcf4

Tsc1

Tsc2

VEGF

WNT1

WNT3

WNT4

wnt5

Wnt7b

Wnt11

OMIM

AD

FEVR

OPPG

osteoarthritis

Parkinson disease

PKD

schizophrenia

tetra-amelia

tuberous sclerosis

FURTHER INFORMATION

Signal Transduction Knowledge Environment

Wnt Gene Homepage

Wnt/β-catenin Pathway Connections Map

Glossary

PLANAR CELL POLARITY

Overt pattern in the plane of the tissue, such as the orientation of hairs or bristles, caused by the subcellular asymmetry in proteins.

RENAL TUBULES

The kidney contains many units known as nephrons, which contain (renal) tubules that are involved in filtering the blood.

ISCHAEMIA

Reduced flow of oxygenated blood to organs in response to blockage in an artery.

URETER

A tube leading from the kidney to the bladder.

FIBROSIS

Formation of fibrous tissue during a repair process.

siRNA

Small interfering RNAs, which target (in a sequence-specific manner) endogenous RNAs for degradation, thereby reducing the function of a gene.

HAIR MATRIX CELL

A cell type at the base of the hair follicle that gives rise to the hair shaft.

MYOCARDIAL INFARCTION

Commonly known as a heart attack, in which there is reduced blood flow to the heart, leading to reduced oxygen supply.

INTESTINAL CRYPT

An involution in the intestine in which stem cells give rise to differentiated cells.

INTRAPERITONEAL

Administered or withdrawn from within the abdominal cavity.

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