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Role of β-Catenin Activation Levels and Fluctuations in Controlling Cell Fate


Role of β-Catenin Activation Levels and Fluctuations in Controlling Cell Fate

Elisa Pedone et al. Genes (Basel).


Cells have developed numerous adaptation mechanisms to external cues by controlling signaling-pathway activity, both qualitatively and quantitatively. The Wnt/β-catenin pathway is a highly conserved signaling pathway involved in many biological processes, including cell proliferation, differentiation, somatic cell reprogramming, development, and cancer. The activity of the Wnt/β-catenin pathway and the temporal dynamics of its effector β-catenin are tightly controlled by complex regulations. The latter encompass feedback loops within the pathway (e.g., a negative feedback loop involving Axin2, a β-catenin transcriptional target) and crosstalk interactions with other signaling pathways. Here, we provide a review shedding light on the coupling between Wnt/β-catenin activation levels and fluctuations across processes and cellular systems; in particular, we focus on development, in vitro pluripotency maintenance, and cancer. Possible mechanisms originating Wnt/β-catenin dynamic behaviors and consequently driving different cellular responses are also reviewed, and new avenues for future research are suggested.

Keywords: cancer; canonical Wnt pathway; development; pluripotency; signaling dynamics; β-catenin.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Overview of the Wnt/β-catenin pathway topology. (A) In the absence of WNT, cytosolic β-catenin is sequestered by the destruction complex and degraded following multiple rounds of phosphorylation and ubiquitination. Low nuclear β-catenin enables the TCF/LEF-mediated repression of target genes. (B) Following WNT ligand stimulation, the destruction complex is inhibited, and β-catenin accumulates. Nuclear β-catenin displaces the repressive complex from the DNA and drives target gene expression in co-operation with TCF/LEF transcription factors. TCF/LEF: T-cell transcription factor/lymphocyte enhancer factor; APC: adenomatous polyposis coli; CK1: casein kinase 1; DVL: dishevelled; FZ: frizzled; GSK3β: glycogen synthase kinase 3; LRP6: low-density lipoprotein receptor-related protein 6; Ub: ubiquitin; GRO: Groucho.
Figure 2
Figure 2
Representative cellular processes influenced by (A) Wnt gradient and (B) time-varying β-catenin levels. The cellular response can depend on both the levels of Wnt/β-catenin pathway activity and on cellular/tissue context. (A) High/intermediate Wnt levels support both intestinal stem-cell (ISC) and β-cell progenitor (βCP) expansion; low Wnt levels stimulate terminal differentiation of enterocytes (EC) and β cells (βC), but sustain hematopoietic stem-cell (HSC) maintenance. Intermediate Wnt levels are mostly associated with blood-cell commitment (T cells, T; myeloid progenitors, MP) and enterocyte-progenitor (ECP) differentiation. (B) β-catenin oscillations control embryo patterning. High or low levels of β-catenin can either promote or impair somatic cell reprogramming, respectively.

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