Receptors

Background: Transmissible gastroenteritis virus (TGEV), a coronavirus (CoV) infecting pigs, uses its spike (S) glycoprotein to bind porcine aminopeptidase N (pAPN) for cell entry. Although structural studies have identified receptor-binding motifs (RBMs) within the receptor-binding domain (RBD) of the S protein, the functional relevance of individual residues for TGEV receptor recognition, cell entry, and infection remain unclear. Methods: In this study, we performed structure-guided mutagenesis of the TGEV RBD to evaluate the contribution of specific residues to receptor binding and viral infectivity. Results: Using soluble RBD proteins, we found that most of the RBD residues within the pAPN-binding interface contribute to the binding interaction. Nonetheless, TGEV reverse genetics experiments revealed that just three RBD residues (Gly527, Tyr528, and Trp571) were indispensable for viral cell entry. Mutations at these positions, which are conserved among group 1 alpha-CoVs abolished infectivity, highlighting their central role in the virus–receptor interface. Conclusions: Our findings provide a detailed functional map of the TGEV RBD and offer insights into the evolution of receptor recognition across CoV.

Multipotent mesenchymal stromal stem cells have captivated the scientific community in recent years due to their ability to differentiate into multiple adult cell types. Central to this potential are many members of the nuclear hormone receptor superfamily, comprising 48 ligand-modulated transcription factors involved in key biological processes such as metabolism, physiology, embryonic development, and reproduction. These transcription factors influence cellular fate by regulating gene expression networks critical for MSC specification, commitment, and differentiation. This review explores the role of nuclear receptors in MSC development, focusing on interactions with chromatin structure, co-regulatory complexes, and responsiveness to extracellular stimuli such as hormones, metabolic cues, and endocrine-disrupting chemicals. We conclude with a discussion of the dangers posed by exogenous and aberrant signaling through nuclear receptors.

The Hedgehog (Hh) signaling pathway regulates key cellular processes, such as proliferation, differentiation, and morphogenesis. Although its canonical activation involves ligand binding to PTCH1, which activates Smoothened (SMO), noncanonical features of the pathway significantly contribute to cancer progression, particularly in prostate cancer (PCa). GLI3, a central transcription factor in the Hh pathway, can act as a repressor or activator depending on posttranslational modifications. In androgen-deprived PCa, GLI3 plays a critical role in driving castration-resistant phenotypes by interacting with the androgen receptor (AR), particularly the AR-V7 variant. This interaction enhances tumor survival and growth even under androgen deprivation therapy (ADT). Aberrant GLI3 activity is further driven by mutations in upstream regulators such as SPOP and MED12, which contribute to the progression of both prostate and other malignancies. Preclinical studies have shown promise in reducing tumor cell proliferation and migration, and in inducing apoptosis, by pharmacologically inhibiting the GLI3 pathway with SMO antagonists or GSK3β inhibitors. Recent evidence also highlights reciprocal interactions between Sonic Hedgehog (Shh) signaling and the AR that sustain tumor growth under ADT. GLI3 engagement with AR reinforces AR-dependent transcription, supporting tumor progression through noncanonical pathways. These findings suggest that targeting GLI3, particularly in combination with AR inhibition, could effectively overcome castration resistance and improve outcomes in patients with castration-resistant prostate cancer (CRPC). This review explores the role of GLI3 in both canonical and noncanonical Hh signaling, its potential as a therapeutic target, and future directions for overcoming resistance in Hh-driven cancers.