Wnt Signaling

The Wnt signaling pathway is a highly conserved and important regulator of cellular processes, including embryonic development, cell proliferation, differentiation, migration, and tissue homeostasis. Wnt signaling coordinates a variety of cellular functions together with various other signaling pathways, and this complex network of interactions ensures precise regulation under physiological and pathological conditions. Wnt closely interacts with Hedgehog (Hh), Notch, Hippo, transforming growth factor-β (TGF-β) /Smad, nuclear factor-κB (NF-κB), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and other pathways.

Wnt, a class of cysteine-rich secretory glycoproteins, is the initiating molecule of signaling pathways. In mammals, there are at least 19 Wnt members that can act on cells in an autocrine or paracrine manner. Post-translational modification of Wnt proteins mainly includes lipid modification and glycosylation, and lipid modification is completed by PORCN. PORCN, located in the endoplasmic reticulum, adds palmitoleate groups to Wnt proteins, which is a key step for the Wnt secretion. Lipid modification is required for Wnt activity and therefore targeting PORCN to inhibit the production of active Wnt proteins is an effective strategy to obstruct Wnt signaling.

Wnt signaling pathways include noncanonical and canonical pathways. Noncanonical Wnt pathways, such as Wnt/ Ca2+ pathway and the Wnt/planar cell polarity (PCP) pathway, are independent of β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF/LEF). The canonical Wnt pathway, also known as the Wnt/ β-catenin pathway, involves nuclear translocation of β-catenin as well as activation of target genes via TCF/LEF transcription factors. The canonical Wnt pathway mainly controls cell proliferation, while the non-canonical Wnt pathway regulates cell polarity and migration. These two major pathways form a network of mutual regulation.

Wnt signaling plays an important role in the self-renewal of certain tissues in mammals. In addition, Wnt signaling is involved liver metabolism and regeneration, lung tissue repair and metabolism, hematopoietic system development, and osteoblast maturation and activity. However, the aberrant activation of Wnt signaling pathway is also a key factor in a variety of diseases, especially cancers. Amerigo Scientific offers a wide range of chemical compounds to facilitate Wnt signaling pathway research for disease mechanism elucidation and drug discovery.

Canonical Wnt/β-catenin Pathway

The canonical Wnt pathway is typically highly conserved and is activated through extracellular Wnt ligands binding to membrane receptors by autocrine/paracrine. Once activated, the canonical Wnt pathway induces the stability of β-catenin and transfers it to the nucleus, ultimately promoting the expression of genes related to cell proliferation, survival, differentiation, and migration. In the absence of Wnt ligands, in the cytoplasm, the "destruction complex" composed of adenomatous polyposis coli (APC), AXIN, casein kinase 1 (CK1), and glycogen synthase kinase 3 protein (GSK-3) captures β-catenin through phosphorylation of CK1 and GSK-3, thereby initiating the degradation of β-catenin.

Glycogen Synthase Kinase 3 (GSK-3) Inhibitors

GSK-3 is a serine-threonine kinase encoded by two isoforms, GSK-3α and GSK-3β, in mammals. With molecular weights of 51 and 47 kDa, respectively, GSK-3α and GSK-3β exhibit similar biochemical and substrate properties. GSK-3 plays a broad role in cellular regulation, mainly because the enzyme controls a wide range of substrates, including cytoplasmic proteins and nuclear transcription factors, such as those associated with Alzheimer's disease, neurological diseases, and cancer.

Casein Kinase 1 (CK1) Inhibitors

CK1 belongs to a subgroup of the serine/threonine protein kinase family. There are six isoforms in the human body: CK1α, γ1, γ2, γ3, δ and ε. CK1 members play a role in Wnt/β-catenin signaling. In contrast to other CK1 family members, CK1α plays a negative role in Wnt pathway regulation. Ck1α phosphorylates β-catenin at Ser45 as part of the β-catenin destruction complex for subsequent β-TrCP-mediated ubiquitination and proteasomal degradation.

CK1 plays an important role in a variety of cellular processes, including regulation of cells, cell survival/apoptosis signaling pathways, and cell division. Studies have shown that CK1 isoforms, including CK1α, CK1γ, CK1δ, and CK1ε, play multiple roles in the development and progression of cancer. Dysregulation of these isoforms leads to various cancer-related processes, including Wnt/β-catenin signaling, circadian disruption, DNA repair, cell cycle progression, and stability of oncogenic proteins.

Tankyrases Inhibitors

Tankyrase belongs to the family of poly (ADP-ribose) polymerases (PARPs), and is widely expressed in human tissues. Tankyrase 1 (PARP5a) and tankyrase 2 (PARP5b) are two isoforms of tankyrase. They are associated with Wnt/β-catenin signaling pathway. In addition, tankyrases also play roles in other cellular processes such as FGFR2 signaling, telomere maintenance, and mitosis.

Inhibiting tankyrases is considered a potential therapeutic approach for cancers with aberrant WNT/β-catenin signaling pathways. Tankyrase is a protein with a molecular weight of 142 kDa that interacts with TRF1, a telomere-specific binding protein that regulates telomere length. The carboxy-terminal region of tankyrase shares homology with the PARP catalytic domain, whereas the central domain of tankyrase consists of 24 ankyrin repeat motifs that mediate interaction with the amino-terminal acidic domain of TRF1.