The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies

Abstract

The canonical WNT/β-catenin signaling pathway governs a myriad of biological processes underlying development and maintenance of adult tissue homeostasis, including regulation of stem cell self-renewal, cell proliferation, differentiation, and apoptosis. WNTs are secreted lipid-modified glycoproteins that act as short-range ligands to activate receptor-mediated signaling pathways. The hallmark of the canonical pathway is the activation of β-catenin mediated transcriptional activity. Canonical WNTs control the β-catenin dynamics as the cytoplasmic level of β-catenin is tightly regulated via phosphorylation by the ‘destruction complex’, consisting of glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), the scaffold protein AXIN, and the tumor suppressor adenomatous polyposis coli (APC). Aberrant regulation of this signaling cascade is associated with varieties of human diseases, especially cancers. Over the past decade, significant progress has been made in understanding the mechanisms of canonical WNT signaling. In this review, we focus on the current understanding of WNT signaling at the extracellular, cytoplasmic membrane, and intracellular/nuclear levels, including the emerging knowledge of crosstalk with other pathways. Recent progresses in developing novel WNT pathway-targeted therapies will also be reviewed. Thus, this review is intended to serve as a refresher of the current understanding about the physiologic and pathogenic roles of WNT/β-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway.

Regulation of β-Catenin Phosphorylation by PR55β in Adenoid Cystic Carcinoma

“…The phosphorylation of β-catenin is regulated by several kinases and phosphatases (7). In the absence of extracellular activation, phosphorylated β-catenin is degraded by proteasomes in the cytoplasm.…”

Upregulated IQUB promotes cell proliferation and migration via activating Akt/GSK3β/β‐catenin signaling pathway in breast cancer

“…When Akt was activated by phosphorylation at Ser473, it could promote phosphorylation of GSK3β at Ser9, which leaded to inactivation of GSK3β 17. GSK3β was the key factor to promote the phosphorylation of β‐catenin at Ser33 and Ser37, which leaded β‐catenin to be degraded by proteasome 6. The inactivation of GSK3β by Ser9 phosphorylation promoted accumulation of β‐catenin and ultimately activated the Wnt/β‐catenin signaling pathway 18.…”

“…Known as the canonical Wnt signaling pathway, Wnt/β‐catenin signaling pathway regulated the early development of embryo, stem cell self‐renewal, cell division, as well as a variety of biological processes such as tumorigenesis and metastasis 6. Aberrant Wnt/β‐catenin signaling pathway frequently occurred in multifarious types of cancers, such as breast cancer7 and colorectal cancer 8.…”

Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity (Review)

“…The Wnt signaling pathway participates in the physiological processes of embryonic development, cellular proliferation and differentiation, and also plays an important role in the occurrence and development of various malignancies (52)(53)(54)(55). Wnt signaling is conducted via three pathways, as follows.…”

“…The network of signaling pathways, including Hh, Wnt, signal transducer and transcription activator (STAT) and NOTCH, contributes to cellular proliferation and differentiation, and to maintaining the stability of the internal environment (14)(15)(16)(52)(53)(54)(55). In invertebrates and lower vertebrates, activation of Wnt and Hh signaling pathways is crucial in embryogenesis and cellular differentiation (70,71).…”