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Review
. 2016 Oct;30(10):3271-3284.
doi: 10.1096/fj.201600502R. Epub 2016 Jun 22.

Wnt/β-catenin pathway in tissue injury: roles in pathology and therapeutic opportunities for regeneration

Dikshya Bastakoty  1 , Pampee P Young  2
Affiliations
Review

Wnt/β-catenin pathway in tissue injury: roles in pathology and therapeutic opportunities for regeneration

Dikshya Bastakoty et al. FASEB J. 2016 Oct.

Abstract

The Wnt/β-catenin pathway is an evolutionarily conserved set of signals with critical roles in embryonic and neonatal development across species. In mammals the pathway is quiescent in many organs VSports手机版. It is reactivated in response to injury and is reported to play complex and contrasting roles in promoting regeneration and fibrosis. We review the current understanding of the role of the Wnt/β-catenin pathway in injury of various mammalian organs and discuss the current advances and potential of Wnt inhibitory therapeutics toward promoting tissue regeneration and reducing fibrosis. -Bastakoty, D. , Young, P. P. Wnt/β-catenin pathway in tissue injury: roles in pathology and therapeutic opportunities for regeneration. .

Keywords: fibrosis; inhibitor; repair; scar; wound healing. V体育安卓版.

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Figures

Figure 1.
Figure 1.
Simplified model of the canonical Wnt pathway and inhibitors. The Wnt–β-catenin pathway consists of secreted glycoproteins (WNT ligands) and Frizzled family of transmembrane receptors or LRP5/6 transmembrane receptors. In the endoplasmic reticulum (ER) of WNT producing cells, the membrane bound O-acyltransferase, Porcupine, acylates the WNT protein. This lipid modification is necessary for secretion of the WNT ligand. The secreted WNT ligand can be sequestered by secreted Frizzled-related protein (sFRP) family of secreted proteins to prevent Wnt ligand binding to receptors. DKK1, another secreted Wnt inhibitor prevents binding of WNT ligand to LRP5/6 receptors. In the absence of extracellular WNT glycoproteins, a destruction complex—including the proteins APC, GSK3β, CK1α, and AXIN—phosphorylates β-catenin, targeting it for ubiquitylation and proteasomal degradation. When WNTs bind to the Frizzled and LRP5/6 coreceptors, Disheveled helps phosphorylate and sequester AXIN to the LRP5/6 receptor, causing disassociation of the β-catenin degradation complex. The stabilized β-catenin enters the nucleus, binds to the TCF family of transcription factors and activates transcription of target genes. Distinct coactivators of transcription such as CBP, the E1A-associated protein p300, Pygopus (PYGO), BCL-9, and Brahma-related gene 1 (BRG1) are involved in the transcription of specific target genes. Independent of TCF, β-catenin can also associate with the FOXO family of transcription factors to activate transcription of genes primarily involved in aging. In the cytoplasm, inhibition of GSK3β activity by WNT ligand binding can simultaneously activate mTOR complex 1 signaling, which results in mRNA translation into proteins. Inhibitors of the pathway and their respective targets are shown in red font on yellow tabs and are further described in Table 1.
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