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. 2016 Mar;3(1):11-40.
doi: 10.1016/j.gendis.2015.12.004. Epub 2016 Jan 14.

Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance

Maryam K Mohammed  1 , Connie Shao  2 , Jing Wang  3 , Qiang Wei  3 , Xin Wang  4 , Zachary Collier  1 , Shengli Tang  5 , Hao Liu  3 , Fugui Zhang  3 , Jiayi Huang  3 , Dan Guo  3 , Minpeng Lu  3 , Feng Liu  3 , Jianxiang Liu  6 , Chao Ma  5 , Lewis L Shi  1 , Aravind Athiviraham  1 , Tong-Chuan He  3 , Michael J Lee  1
Affiliations

Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance

Maryam K Mohammed et al. Genes Dis. 2016 Mar.

Abstract

Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities, including cell proliferation, calcium homeostasis, and cell polarity. The role of Wnt signaling in control of cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway, which is the best characterized among the multiple Wnt signaling branches. The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway, as many new components of Wnt signaling have been identified and linked to signaling regulation, stem cell functions, and adult tissue homeostasis. Additionally, a substantial body of evidence links Wnt signaling to tumorigenesis of many cancer types and implicates it in the development of cancer drug resistance. Thus, a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy. This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease. We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness, tumorigenesis, and cancer drug resistance. Ultimately, we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance.

Keywords: Wnt; cancer; cancer drug resistance; cancer stem cells; canonical Wnt; cell differentiation; cell proliferation; fate determination; self-renewal; signal transduction; stem cells; tumorigenesis; β-catenin.

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Figures

Fig. 1
Fig. 1
The initial upstream signaling components of the Wnt signaling pathways include Frizzled receptor (Fz), co-receptor, and Dishevelled (Dsh). (1) Extracellular binding of Wnt to the cysteine-rich domain (CRD) of Fz leads to membrane localization of a co-receptor which may directly bind the Wnt ligand, and (2) recruitment of the phosphoprotein Dsh to the intracellular membrane leaflet. Dsh activates specific downstream effectors leading to induction of a specific arm of Wnt signaling. The specificity of activation is determined by which domains interact with Fz.
Fig. 2
Fig. 2
Inactivation and proteosomal degradation of β-catenin is inhibited by activation of canonical Wnt signaling. (A) In the absence of canonical Wnt signaling, phosphorylation of β-catenin at key residues by GSK-3 and CK-1 occurs constitutively and is facilitated by the scaffolding proteins APC and Axin. Phosphorylation at N-terminal serine and threonine residues creates a binding site for the ubiquitin ligase SCFβ-TrCP and _targets β-catenin for proteosomal degradation. (B) Activation of canonical Wnt signaling by binding of a canonical Wnt ligand to Fz and LRP-5/6 co-receptor recruits Axin to the inner membrane leaflet via interactions with Dsh and LRP-5/6, thereby disrupting the β-catenin destruction complex. Stable β-catenin is able to accumulate in the cytosolic and nuclear compartments. In the nucleus, β-catenin displaces the co-repressor protein Groucho from TCF/LEF transcription factors and, with the help of co-activators such as CBP or p300 (not pictured) initiates transcription of _target genes.
Fig. 3
Fig. 3
The planar cell polarity (PCP) pathway regulates epithelial cell and tissue polarity by regulating the actin cytoskeleton. Following non-canonical Wnt ligand binding to Fz and co-localization of a co-receptor, Dsh is activated and localized to the inner membrane leaflet. PDZ and DEP domains simultaneously activate small GTPases Rho and Rac through parallel pathways, as well as the actin-binding protein Profilin. Activation of Rho and Profilin occur through a Dishevelled associated activator of morphogenesis 1 (Daam1)-dependent pathway; Rac activation is Daam1-independent. Activation of Rho-associated kinase (ROCK) and myosin occur downstream of Rho activation, leading to modification and rearrangement of the actin cytoskeleton. Rac GTPase activates JNK, whose downstream effects leading to cytoskeletal modification remain poorly characterized. This cytoskeletal modification regulates both the apical-basal polarity of cells and the polarity of cells within an epithelial layer.
Fig. 4
Fig. 4
Activation of the Wnt/Ca2+pathway triggers the release of intracellular calcium stores. In the Wnt/Ca2+ pathway, binding of Wnt ligand to Fz activates G-proteins, which in turn activate Dsh. Activated Dsh binds phosphodiesterase (PDE), which inhibits Protein Kinase G (PKG) and causes an increase in intracellular calcium, as well as the enzyme phospholipase C (PLC). Activated PLC produces inositol triphosphate (IP3) and 1,2-diacylglycerol (DAG) from the membrane-bound phospholipid phosphatidyl inositol 4,5-bisphosphate. IP3 triggers release of intracellular Ca2+ from stores in the endoplasmic reticulum (ER), which activates a number of downstream _targets, including CamKII, calcineurin, and protein kinase C (PKC). Activation of PKC by Ca2+ requires DAG, and leads to phosphorylation and activation of cell division control protein 42 (Cdc42), a GTPase. Activation of calcineurin by Ca2+ and calmodulin (not pictured), dephosphorylates and activates the nuclear factor associated with T cells (NFAT) family of transcription factors, thereby facilitating transcription of their _target genes and linking intracellular Ca2+ signaling to gene expression. _target genes of the NFAT family include genes critical for the immune response, but have also been shown to influence ventral cell fates in vertebrate embryos. Finally, CamKII activation has a downstream effect that includes antagonizing β-catenin/TCF regulated transcription.
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