Signaling by WNT

Stable Identifier
Homo sapiens
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WNT signaling pathways control a wide range of developmental and adult process in metozoans including cell proliferation, cell fate decisions, cell polarity and stem cell maintenance (reviewed in Saito-Diaz et al, 2013; MacDonald et al, 2009). The pathway is named for the WNT ligands, a large family of secreted cysteine-rich glycoproteins. At least 19 WNT members have been identified in humans and mice with distinct expression patterns during development (reviewed in Willert and Nusse, 2012). These ligands can activate at least three different downstream signaling cascades depending on which receptors they engage.
In the so-called 'canonical' WNT signaling pathway, WNT ligands bind one of the 10 human Frizzled (FZD) receptors in conjunction with the LRP5/6 co-receptors to activate a transcriptional cascade that controls processes such as cell fate, proliferation and self-renenwal of stem cells. Engagement of the FZD-LRP receptor by WNT ligand results in the stabilization and translocation of cytosolic beta-catenin to the nucleus where it is a co-activator for LEF (lymphoid enhancer-binding factor)- and TCF (T cell factor) -dependent transcription. In the absence of WNT ligand, cytosolic beta-catenin is phosphorylated by a degradation complex consisting of glycogen synthase kinase 3 (GSK3), casein kinase 1 (CK1), Axin and Adenomatous polyposis coli (APC), and subsequently ubiquitinated and degraded by the 26S proteasome (reviewed in Saito-Diaz et al, 2013; Kimmelman and Xu, 2006).
In addition to the beta-catenin-dependent transcriptional response, WNT signaling can also activate distinct non-transcriptional pathways that regulate cell migration and polarity. These beta-catenin-independent 'non-canonical' pathways signal through Frizzled receptors independently of LRP5/6, or occur through the tyrosine kinase receptors ROR and RYK (reviewed in Veeman et al, 2003; James et al, 2009). Non-canonical WNT pathways are best studied in Drosophila where the planar cell polarity (PCP) pathway controls the orientation of wing hairs and eye facets, but are also involved in processes such as convergent extension, neural tube closure, inner ear development and hair orientation in vertebrates and mammals(reviewed in Seifert and Mlodzik, 2007; Simons and Mlodzik, 2008). In the PCP pathway, binding of WNT ligand to the FZD receptor leads to activation of small Rho GTPases and JNK, which regulate the cytoskeleton and coordinate cell migration and polarity (reviewed in Lai et al, 2009; Schlessinger et al, 2009). In some cases, a FZD-WNT interaction increases intracellular calcium concentration and activates CaMK II and PKC; this WNT calcium pathway promotes cell migration and inhibits the canonical beta-catenin dependent transcriptional pathway (reviewed in Kuhl et al, 2000; Kohn and Moon, 2005; Rao et al 2010). Binding of WNT to ROR or RYK receptors also regulates cell migration, apparently through activation of JNK or SRC kinases, respectively, however the details of these pathways remain to be worked out (reviewed in Minami et al, 2010).
Although the WNT signaling pathways were originally viewed as discrete, linear pathways controlled by defined subsets of 'canonical' or 'non-canonical' ligands and receptors, the emerging evidence is challenging this notion. Instead, the specificity and the downstream response appear to depend on the particular cellular context and vary with species, tissue and stage of development (reviewed in van Amerongen and Nusse, 2009; Rao et al, 2010).
Literature References
PubMed ID Title Journal Year
19365405 Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis

Chien, AJ, Lai, SL, Moon, RT

Cell Res. 2009
19530173 Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases

Oishi, I, Minami, Y, Endo, M, Nishita, M

Dev. Dyn. 2010
19204114 Wnt signaling pathways meet Rho GTPases

Hall, A, Schlessinger, K, Tolwinski, N

Genes Dev. 2009
23256519 The way Wnt works: Components and mechanism

Wang, X, Wallace, HA, Page-McCaw, A, Lee, E, Thorne, CA, Chen, TW, Saito-Diaz, K

Growth Factors 2013
20576942 An updated overview on Wnt signaling pathways: a prelude for more

Kühl, M, Rao, TP

Circ. Res. 2010
16099039 Wnt and calcium signaling: beta-catenin-independent pathways

Moon, RT, Kohn, AD

Cell Calcium 2005
12967557 A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling

Veeman, MT, Moon, RT, Axelrod, JD

Dev. Cell 2003
17143292 beta-catenin destruction complex: insights and questions from a structural perspective

Kimelman, D, Xu, W

Oncogene 2006
17230199 Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility

Seifert, JR, Mlodzik, M

Nat Rev Genet 2007
10858654 The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape

Sheldahl, LC, Kühl, M, Moon, RT, Miller, JR, Park, M

Trends Genet. 2000
22952392 Wnt proteins

Nusse, R, Willert, K

Cold Spring Harb Perspect Biol 2012
18710302 Planar cell polarity signaling: from fly development to human disease

Mlodzik, M, Simons, M

Annu. Rev. Genet. 2008
19619488 Wnt/beta-catenin signaling: components, mechanisms, and diseases

MacDonald, BT, Tamai, K, He, X

Dev Cell 2009
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