WNT signal, through the canonical pathway, controls cell fate determination and through the non-canonical pathway controls cell movement and tissue polarity (1). The name "wnt" is a fusion of two terms, wg derived from the Drosophila gene wingless (wg) and int derived from the proto-oncogene integration-1, which is the mammalian homolog of wg (2).

ß-catenin is the key regulated effector of Wnt, involved in canonical signaling (3). Free ß-catenin is bound by a multiprotein "destruction complex". The ß-catenin destruction complex is comprised of ß-catenin, scaffold proteins (APC, AXIN) and serine/threonine kinases that phosphorylate ß-catenin casein kinase 1 (CSNK1A1, CSNK1D, CSNK1E, CSNK1G1) and GSK3B (1, 3, 4). The sequential phosphorylation of ß-catenin by casein kinase 1 and GSK3 is recognised by an SCF-class E3-ubiquitin ligase, which targets it for polyubiquitination and proteosomal destruction (3).

Canonical WNT signals are transduced through a two-part receptor, a seven-transmembrane Frizzled (FZD) and low density lipoprotein receptor-related protein 5/6 (LRP5/LRP6) to a ß-catenin (CTNNB1) signaling cascade (1, 2, 5, 6). On recruitment of deshevelled (DVL1) to FZD and AXIN to LRP6, ß-catenin destruction complex disassembles leading to its stabilization and nuclear accumulation (1, 7). Nuclear ß-catenin binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors and Legless family docking protein, BCL9. These activate the transcription of Wnt target genes CCND1, MYC(1, 3, 6, 8, 9).

Non-canonical WNT signaling diverges downstream after being transduced through FZD family receptors and co-receptors, ROR2 and RYK. This pathway does not involve ß-catenin-mediated gene expression. Small G proteins such as RAC1, RHOA and downstream effectors of RAC including JNK are DVL-dependant effector molecules of the non-canonical pathway (1, 7). These have been implicated in cytoskeletal rearrangement (1), dendrite growth (7, 10) and control of cell polarity and orientation (7). Nemo-like kinase (NLK) and nuclear factor of activated T cells (NFAT) are Ca2+-dependant effectors of the non-canonical pathway. NLK inhibits canonical pathway by phosphorylation of TCF/LEF family transcription factors. NFAT transcription factor is implicated in convergent extension during early embryogenesis and carcinogenic metastasis (7).

References

1. Katoh M, Katoh M (2007) WNT Signaling Pathway and Stem Cell Signaling Network. Clin Cancer Res, 13(14): 4042-5.

2. Wend P, Hollan JD, Ziebold U, Birchmeier W (2010) Wnt Signaling in Stem and Cancer Stem Cells. Semin Cell Dev Biol, 21(8): 855-63.

3. Cadigan KM, Peifer M (2009) Wnt Signaling from Development to Disease: Insights from Model Systems. Cold Spring Harb Perspect Biol, 1(2):a002881.

4. Sakanaka C, Weiss JB, Williams LT (1998) Bridging of beta-catenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription. Proc Natl Acad Sci U S A, 95(6): 3020-3.

5. Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J, Nusse R (1996) A New Member of the Frizzled Family from Drosophila Functions as a Wingless Receptor. Nature, 382(6588):225-30.

6. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC. (2000) An LDL-receptor-related protein mediates Wnt signaling in mice. Nature, 407(6803): 535-8.

7. Gao C, Chen YG (2010) Dishevelled: The hub of Wnt signaling. Cellular Signaling, 22:717-27.

8. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P (1997) Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science, 275(5307):1790-2.

9. Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, Murone M, Züllig S, Basler K (2002) Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell, 109(1): 47-60.

10. Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC (2005) Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat Neurosci, 8(1): 34-42.