Most physiologic processes in the brain and related diseases involve more than one neurotransmitter system. Thus, elucidation of the interaction between different neurotransmitter systems could allow for better therapeutic approaches to the treatments of related diseases. Dopaminergic (DAergic) and cholinergic neurotransmitter system regulate various brain functions that include cognition, movement, emotion, etc. This review focuses on the interaction between the brain DAergic and cholinergic systems with respect to the pathogenesis and treatment of schizophrenia and Parkinson’s disease (PD). We first discussed the selection of motor plans at the level of basal ganglia, the major DAergic and cholinergic pathways in the brain, and the receptor subtypes involved in the interaction between the two signaling systems. Next, the roles of each signaling system were discussed in the context of the negative symptoms of schizophrenia, with a focus on the α7 nicotinic cholinergic receptor and the dopamine D₁ receptor in the prefrontal cortex. In addition, the roles of the nicotinic and dopamine receptors were discussed in the context of regulation of striatal cholinergic interneurons, which play crucial roles in the degeneration of nigrostriatal DAergic neurons and the development of L-DOPA-induced dyskinesia in PD patients. Finally, we discussed the general mechanisms of nicotine-induced protection of DAergic neurons.

MYB, a proto-oncogene, is overexpressed in prostate cancer (PCa) and promotes its growth, aggressiveness, and resistance to androgen-deprivation therapy. Here, we examined the effect of androgen signaling on MYB expression and delineated the underlying molecular mechanisms. Paralleling a dichotomous effect on growth, low-dose androgen induced MYB expression at both transcript and protein levels, whereas it was suppressed in high-dose androgen-treated PCa cells. Interestingly, treatment with both low- and high-dose androgen transcriptionally upregulated MYB by increasing the binding of androgen receptor to the MYB promoter. In a time-course assay, androgen induced MYB expression at early time points followed by a sharp decline in high-dose androgen-treated cells due to decreased stability of MYB mRNA. Additionally, profiling of MYB-targeted miRNAs demonstrated significant induction of miR-150 in high-dose androgen-treated PCa cells. We observed a differential binding of androgen receptor on miR-150 promoter with significantly greater occupancy recorded in high-dose androgen-treated cells than those treated with low-dose androgen. Functional inhibition of miR-150 relieved MYB suppression by high-dose androgen, while miR-150 mimic abolished MYB induction by low-dose androgen. Furthermore, MYB-silencing or miR-150 mimic transfection suppressed PCa cell growth induced by low-dose androgen, whereas miR-150 inhibition rescued PCa cells from growth repression by high-dose androgen. Similarly, we observed that MYB silencing suppressed the expression of androgen-responsive, cell cycle–related genes in low-dose androgen-treated cells, while miR-150 inhibition increased their expression in cells treated with high-dose androgen. Overall, these findings reveal novel androgen-mediated mechanisms of MYB regulation that support its biphasic growth control in PCa cells.

A class-A GPCR dopamine D2 receptor (D2R) plays a critical role in the proper functioning of neuronal circuits through the downstream activation of both G-protein- and β-arrestin-dependent signaling pathways. Understanding the signaling pathways downstream of D2R is critical for developing effective therapies with which to treat dopamine (DA)-related disorders such as Parkinson’s disease and schizophrenia. Extensive studies have focused on the regulation of D2R-mediated extracellular-signal-regulated kinase (ERK) 1/2 signaling; however, the manner in which ERKs are activated upon the stimulation of a specific signaling pathway of D2R remains unclear. The present study conducted a variety of experimental techniques, including loss-of-function experiments, site-directed mutagenesis, and the determination of protein interactions, in order to investigate the mechanisms underlying β-arrestin-biased signaling-pathway-mediated ERK activation. We found that the stimulation of the D2R β-arrestin signaling pathway caused Mdm2, an E3 ubiquitin ligase, to move from the nucleus to the cytoplasm and interact with tyrosine phosphorylated G-protein-coupled receptor kinase 2 (GRK2), which was facilitated by Src, a non-receptor tyrosine kinase. This interaction led to the ubiquitination of GRK2, which then moved to the plasma membrane and interacted with activated D2R, followed by the phosphorylation of D2R as well as the mediation of ERK activation. In conclusion, Mdm2-mediated GRK2 ubiquitination, which is selectively triggered by the stimulation of the D2R β-arrestin signaling pathway, is necessary for GRK2 membrane translocation and its interaction with D2R, which in turn mediates downstream ERK signaling. This study is primarily novel and provides essential information with which to better understand the detailed mechanisms of D2R-dependent signaling.

Smokeless tobacco (ST) is an alternative to smoking, which involves not the burning of tobacco. Although ST has been used for thousands of years, its health effects are not well characterized, and it is the subject of misconceptions throughout society. Therefore, it is crucial to identify the risks associated with ST use. We conducted a comprehensive search of the scientific literature to identify studies reporting associations between tobacco chewing and the risk of oral cancer and premalignant lesions. Our review discusses the molecular mechanisms associated with ST components, along with the role of ST use in speech impairment and cancer progression. We also examine the effectiveness of tobacco cessation strategies and review the existing perceptions held by ST consumers. Our findings indicate significant health risks associated with ST use, including increased cancer risk and speech impairments. As societal perceptions and misconceptions about ST are important factors that influence its use, there is a need for comprehensive public awareness campaigns to correct these misconceptions and to promote healthier lifestyle choices. We call for further research to improve cessation interventions and to increase public awareness of relevant research discoveries. By providing a thorough discussion of the health impacts of ST, we aim to inform policy decisions and public health strategies to reduce the prevalence of ST use.

Multiomics approaches and integrative analyses have enabled the identification of molecular signatures that drive oncogenic transcriptional programs, reshape the tumor microenvironment, and promote metastatic dissemination. These tools are revealing an unprecedented level of complexity in receptorligand interactions and signaling plasticity across diverse cancer types. Consequently, these insights are not only redefining the molecular taxonomy of tumors but also accelerating the development of nextgeneration therapeutics, ranging from allosteric inhibitors and antibody-drug conjugates to chimeric antigen receptor (CAR) T-cells and bispecific antibodies to improve clinical management. As we continue to dissect how receptor signaling networks are rewired during tumor evolution and therapy resistance, a systems-level understanding will be essential for designing durable, patient-tailored interventions.The articles in this special issue showcase how diverse scientific approaches are converging on a unified insight: cancer signaling is best understood as a dynamic, multilayered network rather than an isolated pathway. A recurrent theme in this collection is the ability of tumors to convert physical cues into biochemical programs. Mechanosensing receptors such as integrin β4 translate extracellular matrix interactions into oncogenic cascades that promote epithelial-mesenchymal transitions (EMT), migration, and therapeutic resistance (Huang et al., 2025). Upon detachment from their structural anchors, these receptors function as signaling scaffolds that cooperate with binding partners to amplify AKT, mitogenactivated protein kinase (MAPK), and Src -focal adhesion kinase (Src-FAK) pathways, creating a signaling architecture optimized for metastatic dissemination. This work underscores a growing realization that mechanical cues are central to how malignant cells acquire invasive behavior.During oncogenesis, key signaling networks acquire another dimension from developmental biology. Pathways that guide embryonic morphogenesis, including Hedgehog, transforming growth factor-β (TGFβ), Notch, and KRAS-driven circuits, are frequently redeployed in pancreatic malignancies. As described by Swain, Narayan, and Mishra (2025), these developmental programs create lineage-specific vulnerabilities, drive cellular plasticity, and foster therapeutic-resistant niches. Tumors, in essence, borrow the logic of early organ formation to construct microenvironments favorable to growth, thereby evading constraints normally imposed on adult tissues.Moreover, even the most sophisticated signaling pathways depend on the broader regulatory environment. For example, lysine acetylation of histones and non-histone proteins can powerfully shape how cells perceive and respond to receptor-derived stimuli. Li and Xue (2025) highlight how altered acetylation states in digestive tract cancers restructure chromatin accessibility, alter protein stability, and recalibrate downstream pathway output. This regulatory layer shows that similar receptor signals can drive distinct transcriptional and phenotypic consequences across tissues and disease contexts.Adding further nuance, alternative splicing generates receptor isoforms with distinct signaling capabilities. CD44, a multifunctional adhesion and signaling receptor long recognized for its complexity, exemplifies this characteristic. Variant isoforms, such as those containing v3, v6, or v9, can alter ligand affinity, change receptor-partner interactions, and reshape downstream stress responses. Yanova et al. (2025) demonstrate how these isoforms regulate apoptosis, autophagy, and ferroptosis, thereby shaping chemoresistance across multiple cancer types. Here, RNA processing becomes a driver of signaling plasticity, enabling tumors to adapt rapidly under therapeutic pressure.Among key GPCRs, the Frizzled (FZD) family of Wnt receptors remains mechanistically challenging, with unresolved questions about ligand specificity, receptor conformation dynamics, and intracellular coupling. Martinez-Marin et al. (2025) review structural and functional advances that clarify how FZD receptors shape canonical and non-canonical Wnt signaling outputs, and highlight receptor complexity as a longstanding barrier to drug development. As structural resolution improves, opportunities are emerging to rationally target Wnt signaling, one of cancer's most notoriously difficult pathways, with improved precision.Within the cell, cytoskeletal regulators act as crucial integrators, linking receptor activation to changes in cell shape, polarity, and motility. The epithelial cell transformation factor 2 (ECT2)-RhoA-Rhoassociated protein kinase (ROCK) axis, as described by Sheng et al. (2025), illustrates how alterations in polarity and contractility amplify oncogenic signaling and promote invasion in gynecologic malignancies. The cytoskeleton, in this sense, is not merely an architectural scaffold but a dynamic signaling hub that modulates how tumors respond to extracellular cues.Importantly, signaling adaptation is also shaped by receptor routing and trafficking. Endosomal signaling and receptor internalization determine the strength, duration, and spatial organization of pathway activation, and thus can contribute to therapeutic resistance and metastatic propensity. Consistent with this, Zhu et al. (2025) show that altered RAB5B (an early endosomal guanosine triphosphatase (GTPase)) expression correlates with key malignant features, including immune infiltration, genomic instability, metastatic potential, and responsiveness to immunotherapy. In parallel, immune checkpoint receptor rewiring under therapeutic pressure highlights signaling plasticity, enabling tumors to remodel immune pathways and evade immune control. Together, these observations highlight that receptor signaling plasticity is not just confined to membrane activation events but also extends across intracellular trafficking...