When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex

Abstract

The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a “canonical” Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers.

Changes Induced by P2X7 Receptor Stimulation of Human Glioblastoma Stem Cells in the Proteome of Extracellular Vesicles Isolated from Their Secretome

“…Thus, in both EV fractions, there was an almost similar and higher percentage of proteins related to cytoskeletal regulation by Rho GTPase, which has widely been associated with human cancer [55,56]. The other proteins were mainly related, although each at a small percentage, to ATP synthesis and glycolysis, inflammatory pathways, some neurodegenerative diseases, and also signals, including integrin, cadherin, FAS, FGF, and Wnt pathways, which are, in turn, coupled to cancer enhancement and progression [57][58][59]. Lastly, in EXOs, a small percentage of proteins was also linked to G protein activated-pathways.…”

“…cancer enhancement and progression [57][58][59]. Lastly, in EXOs, a small percentage o teins was also linked to G protein activated-pathways.…”

Hair follicle stem cells promote epidermal regeneration under expanded condition

“…Research has identified a versatile population of HFSCs are situated close to the sebaceous gland. These cells are referred to HF-associated pluripotent stem cells, and their offspring are located in the outer root sheath of the HF ( Li et al, 2023 ; Amoh and Hoffman, 2017 ). Stem cells in the upper bulge area, usually dormant but with self-renewal capabilities, are the primary source for the upper hair and sebaceous unit ( Rompolas et al, 2013 ).…”

“…The Wnt protein family is encoded by the wnt gene, which initiates complex cascade signaling reactions by binding to Frizzled membrane protein receptors and ultimately regulates the transcriptional activation of target genes. Wnt signals are transmitted through at least three different intracellular pathways, with the classical Wnt/β-catenin signal having a close relationship with HFSCs ( Li et al, 2023 ). The Frizzled receptors are bound by the Wnt ligand, which in turn leads to the anchoring of Axin to the phosphorylated lipoprotein receptor-related protein ( Ren et al, 2021 ).…”

GSK3 as a Master Regulator of Cellular Processes

“…The central regulatory principle of GSK3 is the modulation of its activity by inhibitory phosphorylation in response to cellular stimulation with tumor necrosis factor, insulin, and multiple growth factors (amongst others) [6]. For Wnt ("wingless-type MMTV integration site family member") glycoproteins, however, phosphorylation-independent mechanisms of GSK3 inactivation have been demonstrated based on GSK3 sequestration in vesicles [7] and the altered composition of GSK3-containing protein complexes [8]. Essential physiological functions directed by GSK3α and β comprise gene expression, metabolism, proliferation, differentiation/development, apoptosis, adhesion, and migration, amongst other things [6].…”