WNT signalling: mechanisms and therapeutic opportunities

Abstract

At the same time as the mechanistic understanding of the WNT signalling system, with its family of 19 secreted lipoglycoproteins, 10 class Frizzled GPCRs (FZD 1-10 ), several single transmembrane-spanning receptors [LDL receptorrelated protein 5/6 (LRP5/6), ROR1/2, RYK and PTK7] and a plethora of extracellular modulators [Dickkopfs (DKKs), SFRPs, WIFs, etc.] at the core of the pathway, is improving it becomes obvious that targeting this system therapeutically comes both with great potential and substantial challenges. This themed section about WNT signalling in the British Journal of Pharmacology aims to underline the progress in our more and more detailed understanding of signalling mechanisms, to summarize emerging concepts for therapy and to highlight novel developments with therapeutic potential. In addition, we aim to bridge the scientific disciplines of cell biology, developmental biology, stem cell biology, oncology, drug development and pharmacology in order to promote a truly translational approach with the goal of obtaining more effective drugs, with higher selectivity and less unwanted side effects, for treating various human diseases. WNT2016@Brno -The 2016International WNT Meeting at Masaryk University, Brno, CZThe WNT meeting in Brno, the city of Gregor Johann Mendel, the founder of genetics, was a continuation of the EMBO conference series on WNT signalling and provided a broad overview of the exciting developments in the research field ranging from deeper structural and molecular insights to disease mechanisms and novel drug targets. In addition, this meeting marks the end of a successful international training network (WntsApp -www.wntsapp.eu) funded by the frame programme FP7 and the Marie Curie Actions/European Commission, in which several members of the conference's organizing committee and participants collaborated. Given the substantial and exciting progress in areas such as establishment and use of organoid cultures, receptor dynamics, WNT secretion, stem cell regulation, single-cell sequencing, novel treatment paradigms for human disease and drug development, an atmosphere of optimism and ambition was present at the meeting. The

The GSK‑3β/β‑catenin signaling pathway is involved in HMGB1‑induced chondrocyte apoptosis and cartilage matrix degradation

“…Wnt signaling regulation of β-catenin plays critical role in variety of physiological processes (41). Previous studies have demonstrated that the expression level of β-catenin was upregulated in degenerative chondrocytes, resulting in loss of cartilage (42,43).…”

Advancing stroke therapy: A deep dive into early phase of ischemic stroke and recanalization

“…The Wnt signaling pathway is a complex network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals 56,57 . Wnt proteins bind to receptors of the Frizzled family and several co‐receptors such as low‐density lipoprotein receptor‐related proteins 5 and 6 (LRP5 and LRP6), Ryk, or Ror2 58,59 .…”

Activation of Wnt/Beta-Catenin Signaling Pathway as a Promising Therapeutic Candidate for Cerebral Ischemia/Reperfusion Injury

“…The Wnt signaling pathway is widely found in invertebrates and vertebrates and is a highly evolutionarily conserved signaling pathway. It plays a crucial role in the early development of embryos, organogenesis, and maintenance of normal physiological functions in adults ( Schulte and Bryja, 2017 ; Jean LeBlanc et al, 2019 ; Routledge and Scholpp, 2019 ).…”

“…The above studies suggest that the ischemic penumbra still has great therapeutic potential for neuroprotection. The Wnt pathway is part of an evolutionarily conserved intracellular signal transduction cascade that regulates multiple processes crucial for cell proliferation, differentiation, migration, and fate decision during development ( Schulte and Bryja, 2017 ; Eubelen et al, 2018 ). Recently, several studies have reported the mechanism by which Wnt/β-catenin signaling is regulated in the adult brain and serves as an endogenous protective mechanism against the central nervous system (CNS) diseases ( Schulte and Bryja, 2017 ; Menet et al, 2020 ; Cheng et al, 2022 ).…”

“…The Wnt pathway is part of an evolutionarily conserved intracellular signal transduction cascade that regulates multiple processes crucial for cell proliferation, differentiation, migration, and fate decision during development ( Schulte and Bryja, 2017 ; Eubelen et al, 2018 ). Recently, several studies have reported the mechanism by which Wnt/β-catenin signaling is regulated in the adult brain and serves as an endogenous protective mechanism against the central nervous system (CNS) diseases ( Schulte and Bryja, 2017 ; Menet et al, 2020 ; Cheng et al, 2022 ). In this review, we discuss the recent research updates on the regulatory mechanism of the classical Wnt (Wnt/β-catenin) signaling pathway and summarize the biological functions of the cells (endothelial cells, neurons, oligodendrocytes, microglia, and astrocytes) affected by stroke pathology.…”