Search Results (51)

The MET oncogene, encoding the hepatocyte growth factor (HGF) receptor, plays a key role in tumorigenesis, invasion, and resistance to therapy, yet its full biological functions and activation mechanisms remain incompletely understood. A feature of MET is its extensive interaction network, encompassing the following: (i) receptor tyrosine kinases (RTKs); (ii) co-receptors (e.g., CDCP1, Neuropilin1); (iii) adhesion molecules (e.g., integrins, tetraspanins); (iv) proteases (e.g., ADAM10); and (v) other receptors (e.g., CD44, plexins, GPCRs, and NMDAR). These interactions dynamically modulate MET’s activation, signaling, intracellular trafficking, and degradation, enhancing its functional versatility and oncogenic potential. This review offers current knowledge on MET’s partnerships, focusing on their functional impact on signaling output, therapeutic resistance, and cellular behavior. Finally, we evaluate emerging combination therapies targeting MET and its interactors, highlighting their potential to overcome resistance and improve clinical outcomes. By exploring the complex interplay within the MET network of interacting cell surface proteins, this review provides insights into advancing anti-cancer strategies and understanding the broader implications of RTK crosstalk in oncology. Full article

Semaphorins are an immunoregulatory protein family. Plexins bind semaphorins (SEMAs) and can form receptor complexes that give them chemotactic capacity. The role and expression profile of semaphorins and plexins in inflammatory bowel disease (IBD) is currently unknown. Aim: Characterize the semaphorins and plexins gene and protein expression in intestinal tissue from IBD patients and correlate them with the clinical phenotype. Material and Methods: This comparative and cross-sectional study enrolled 54 diagnosed IBD patients and 20 controls. Gene and protein expression of semaphorins and plexins were determined by RT-PCR and IHQ for the co-localization with neutrophils (myeloperoxidase, MPO) or CD123 plasmacytoid dendritic cells in intestinal tissue from IBD patients. Results: Colonic mucosa from active and remission ulcerative colitis (UC) had a significantly lower SEMA4D and PLXNA1, but higher PLXNB1 gene expression than the control group. The only significant difference between active UC and remission was observed in the higher gene expression of SEMA6D in remission. It was associated with histological remission (p = 0.01, OR = 15, 95% CI: 1.39–16.1). The low expression of PLXNA1 was associated with mild intermittent activity with two relapses per year (p = 0.003, OR = 0.05, CI = 0.006–0.51). Higher SEMA4D+ positive cells were detected in the submucosa, while PLXNC1+/MPO+ in the mucosal and submucosa of active UC patients compared with controls. Conclusions: The increased expression of the semaphorin and plexin family in IBD patients suggests their immunoregulatory function and is associated with remission and clinical phenotype in patients with UC. Full article

The present study aims to evaluate the effect of a dietary supplementation with 10% grape pomace (GP) on the whole blood transcriptome of lactating ewes. By applying a log₂FC higher than 0.5 or lower than −0.5 and a false discovery rate (FDR) <0.05, the down-regulation of genes coding for plexin C1, ethanolamine kinase 1, tax1-binding protein 1, transmembrane 9 superfamily member 2, and Beclin-1 was observed in animals that received the dietary supplementation. This aspect was also accompanied by a reduction in the blood activity of matrix metalloproteinase 9 (MMP-9; p < 0.05), a gelatinase commonly involved in both acute and chronic pathological events. The ELISA test on other factors involved in inflammatory processes, interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α), as well as in the antioxidant response, glutathione peroxidase (GPx), and catalase (CAT), did not reveal any significant changes (p > 0.05). Overall, the introduction of GP in the diet of ewes gave indications of greater efficacy in preserving animal welfare, with interesting cues regarding the valorization of a by-product with a high biological value. Full article

Glaesserella parasuis (G. parasuis) causes serious inflammation and meningitis in piglets. Quercetin has anti-inflammatory and anti-bacterial activities; however, whether quercetin can alleviate brain inflammation and provide protective effects during G. parasuis infection has not been studied. Here, we established a mouse model of G. parasuis infection in vivo and in vitro to investigate transcriptome changes in the mouse cerebrum and determine the protective effects of quercetin on brain inflammation and blood–brain barrier (BBB) integrity during G. parasuis infection. The results showed that G. parasuis induced brain inflammation, destroyed BBB integrity, and suppressed PI3K/Akt/Erk signaling-pathway activation in mice. Quercetin decreased the expression of inflammatory cytokines (Il-18, Il-6, Il-8, and Tnf-α) and BBB-permeability marker genes (Mmp9, Vegf, Ang-2, and Et-1), increased the expression of angiogenetic genes (Sema4D and PlexinB1), reduced G. parasuis-induced tight junction disruption, and reactivated G. parasuis-induced suppression of the PI3K/Akt/Erk signaling pathway in vitro. Thus, we concluded that quercetin may protect BBB integrity via the PI3K/Akt/Erk signaling pathway during G. parasuis infection. This was the first attempt to explore the protective effects of quercetin on brain inflammation and BBB integrity in a G. parasuis-infected mouse model. Our findings indicated that quercetin is a promising natural agent for the prevention and treatment of G. parasuis infection. Full article

Caveolin-1 (Cav1) is a major plasma membrane protein that plays important functions in cellular metabolism, proliferation, and senescence. Mice lacking Cav1 show abnormal gene expression in the fetal brain. Though evidence for placental influence on brain development is emerging, whether the ablation of Cav1 affects the regulation of the brain–placental axis remains unexamined. The current study tests the hypothesis that gene expression changes in specific cells of the placenta and the fetal brain are linked to the deregulation of the brain–placental axis in Cav1-null mice. By performing single-nuclei RNA sequencing (snRNA-seq) analyses, we show that the abundance of the extravillious trophoblast (EVT) and stromal cells, but not the cytotrophoblast (CTB) or syncytiotrophoblast (STB), are significantly impacted due to Cav1 ablation in mice. Interestingly, specific genes related to brain development and neurogenesis were significantly differentially expressed in trophoblast cells due to Cav1 deletion. Comparison of single-cell gene expression between the placenta and the fetal brain further showed that specific genes such as plexin A1 (Plxna1), phosphatase and actin regulator 1 (Phactr1) and amyloid precursor-like protein 2 (Aplp2) were differentially expressed between the EVT and STB cells of the placenta, and also, between the radial glia and ependymal cells of the fetal brain. Bulk RNA-seq analysis of the whole placenta and the fetal brain further identified genes differentially expressed in a similar manner between the placenta and the fetal brain due to the absence of Cav1. The deconvolution of reference cell types from the bulk RNA-seq data further showed that the loss of Cav1 impacted the abundance of EVT cells relative to the stromal cells in the placenta, and that of the glia cells relative to the neuronal cells in the fetal brain. Together, the results of this study suggest that the ablation of Cav1 causes deregulated gene expression in specific cell types of the placenta and the fetal brain in mice. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes autism, Asperger’s syndrome, and pervasive developmental disorder. ASD is characterized by poor interpersonal relationships and strong attachment. The correlations between activated or inactivated gene products, which occur as a result of genetic mutations affecting neurons in ASD patients, and ASD symptoms are now of critical concern. Here, for the first time, we describe the process in which that the respective ASD-associated mutations (Arg676-to-Cys [R676C] and Ser951-to-Cys [S951C]) of semaphorin-5A (Sema5A) localize Sema5A proteins themselves around the plasma membrane in the N1E-115 cell line, a model line that can achieve neuronal morphological differentiation. The expression of each mutated construct resulted in the promotion of excessive elongation of neurite-like processes with increased differentiation protein markers; R676C was more effective than S951C. The differentiated phenotypes were very partially neutralized by an antibody, against Plexin-B3 as the specific Sema5A receptor, suggesting that the effects of Sema5A act in an autocrine manner. R676C greatly increased the activation of c-Jun N-terminal kinase (JNK), one of the signaling molecules underlying process elongation. In contrast, the blocking of JNK signaling, by a chemical JNK inhibitor or an inhibitory construct of the interaction of RhoG with Elmo1 as JNK upstream signaling molecules, recovered the excessive process elongation. These results suggest that ASD-associated mutations of Sema5A, acting through the JNK signaling cascade, lead to excessive differentiated phenotypes, and the inhibition of JNK signaling recovers them, revealing possible therapeutic targets for recovering the potential molecular and cellular phenotypes underlying certain ASD symptoms. Full article

According to recent evidence, some groups of semaphorins (SEMAs) have been associated with cancer progression. These proteins are able to modulate the cellular signaling of particular receptor tyrosine kinases (RTKs) via the stimulation of SEMA-specific coreceptors, namely plexins (plexin-A, -B, -C, -D) and neuropilins (Np1, Np2), which share common domains with RTKs, leading to the coactivation of the latter receptors. MET, ERBB2, VEGFR2, PFGFR, and EGFR, among others, represent acknowledged targets of semaphorins that are often associated with tumor progression or poor prognosis. In particular, higher expression of SEMA6 family proteins in cancer cells and stromal cells of the cancer niche is often associated with enhanced tumor angiogenesis, metastasis, and resistance to anticancer therapy. Notably, high SEMA6 expression in malignant tumor cells such as melanoma, pleural mesothelioma, gastric cancer, lung adenocarcinoma, and glioblastoma may serve as a prognostic biomarker of tumor progression. To date, very few studies have focused on the mechanisms of transmembrane SEMA6-driven tumor progression and its underlying interplay with RTKs within the tumor microenvironment. This review presents the growing evidence in the literature on the complex and shaping role of SEMA6 family proteins in cancer responsiveness to environmental stimuli. Full article

In recent years, olfactory dysfunction has attracted increasingly more attention as a hallmark symptom of neurodegenerative diseases (ND). Deeply understanding the molecular basis underlying the development of the olfactory bulb (OB) will provide important insights for ND studies and treatments. Now, with a genetic knockout mouse model, we show that TRIM67, a new member of the tripartite motif (TRIM) protein family, plays an important role in regulating the proliferation and development of mitral cells in the OB. TRIM67 is abundantly expressed in the mitral cell layer of the OB. The genetic deletion of TRIM67 in mice leads to excessive proliferation of mitral cells in the OB and defects in its synaptic development, resulting in reduced olfactory function in mice. Finally, we show that TRIM67 may achieve its effect on mitral cells by regulating the Semaphorin 7A/Plexin C1 (Sema7A/PlxnC1) signaling pathway. Full article

Breast cancer is the most common cancer worldwide and a leading cause of cancer-related deaths in women. The clinical management of breast cancer is further complicated by the heterogeneous nature of the disease, which results in varying prognoses and treatment responses in patients. The semaphorins are a family of proteins with varied roles in development and homoeostasis. They are also expressed in a wide range of human cancers and are implicated as regulators of tumour growth, angiogenesis, metastasis and immune evasion. More recently, semaphorins have been implicated in drug resistance across a range of malignancies. In breast cancer, semaphorins are associated with resistance to endocrine therapy as well as breast cancer chemotherapeutic agents such as taxanes and anthracyclines. This review will focus on the semaphorins involved in breast cancer progression and their association with drug resistance. Full article

Plexins are a family of nine single-pass transmembrane receptors with a conserved GTPase activating protein (GAP) domain. The plexin family is divided into four subfamilies: Type-A, type-B, type-C, and type-D plexins. Plexins function as receptors for axon guidance factors of the semaphorin family. The semaphorin gene family contains 22 genes that are divided into eight subclasses of which subclasses three to seven represent vertebrate semaphorins. The plexins and their semaphorin ligands have important roles as regulators of angiogenesis, cancer proliferation, and metastasis. Class 3 semaphorins, with the exception of sema3E, are the only semaphorins that do not bind directly to plexins. In order to transduce their signals, they bind instead to complexes consisting of receptors of the neuropilin family and various plexins. Some plexins also form complexes with tyrosine-kinase receptors such as the epidermal growth factor receptor ErbB2, the mesenchymal epithelial transition factor receptor (MET), and the Vascular endothelial growth factor receptor 2 (VEGFR2) and, as a result, can modulate cell proliferation and tumor progression. This review focuses on the roles of the different plexins in the control of cancer cell proliferation and invasiveness. Plexins also affect tumor progression and tumor metastasis by indirect mechanisms, such as modulation of angiogenesis and immune responses. However, these topics are not covered in the present review. Full article

This work aimed to evaluate the effect of Semaphorin 4D (SEMA4D) signaling through Plexin B1 on the vasculogenic differentiation of dental pulp stem cells. We assessed the protein expression of SEMA4D and Plexin B1 in dental pulp stem cells (DPSC) from permanent human teeth and stem cells from human exfoliated deciduous (SHED) teeth using Western blots. Their expression in human dental pulp tissues and DPSC-engineered dental pulps was determined using immunofluorescence. We then exposed dental pulp stem cells to recombinant human SEMA4D (rhSEMA4D), evaluated the expression of endothelial cell differentiation markers, and assessed the vasculogenic potential of rhSEMA4D using an in vitro sprouting assay. Lastly, Plexin B1 was silenced to ascertain its role in SEMA4D-mediated vasculogenic differentiation. We found that SEMA4D and Plexin B1 are expressed in DPSC, SHED, and human dental pulp tissues. rhSEMA4D (25–100 ng/mL) induced the expression of endothelial markers, i.e., vascular endothelial growth factor receptor (VEGFR)-2, cluster of differentiation (CD)-31, and tyrosine kinase with immunoglobulin-like and EGF-like domains (Tie)-2, in dental pulp stem cells and promoted capillary-like sprouting in vitro (p < 0.05). Furthermore, Plexin B1 silencing abrogated the vasculogenic differentiation of dental pulp stem cells and significantly inhibited capillary sprouting upon exposure to rhSEMA4D. Collectively, these data provide evidence that SEMA4D induces vasculogenic differentiation of dental pulp stem cells through Plexin B1 signaling. Full article

Estrogen receptor positive (ER⁺) breast cancer (BCa) accounts for the highest proportion of breast cancer-related deaths. While endocrine therapy is highly effective for this subpopulation, endocrine resistance remains a major challenge and the identification of novel targets is urgently needed. Previously, we have shown that Semaphorin 3C (SEMA3C) is an autocrine growth factor that drives the growth and treatment resistance of various cancers, but its role in breast cancer progression and endocrine resistance is poorly understood. Here, we report that SEMA3C plays a role in maintaining the growth of ER⁺ BCa cells and is a novel, tractable therapeutic target for the treatment of ER⁺ BCa patients. Analyses of publicly available clinical datasets indicate that ER⁺ BCa patients express significantly higher levels of SEMA3C mRNA than other subtypes. Furthermore, SEMA3C mRNA expression was positively correlated with ESR1 mRNA expression. ER+ BCa cell lines (MCF7 and T47D) expressed higher levels of SEMA3C mRNA and protein than a normal mammary epithelial MCF10A cell line. ER siRNA knockdown was suppressed, while dose-dependent beta-estradiol treatment induced SEMA3C expression in both MCF7 and T47D cells, suggesting that SEMA3C is an ER-regulated gene. The stimulation of ER⁺ BCa cells with recombinant SEMA3C activated MAPK and AKT signaling in a dose-dependent manner. Conversely, SEMA3C silencing inhibited Estrogen Receptor (ER) expression, MAPK and AKT signaling pathways while simultaneously inducing apoptosis, as monitored by flow cytometry and Western blot analyses. SEMA3C silencing significantly inhibited the growth of ER⁺ BCa cells, implicating a growth dependency of ER⁺ BCa cells on SEMA3C. Moreover, the analysis of tamoxifen resistant (TamR) cell models (TamC3 and TamR3) showed that SEMA3C levels remain high despite treatment with tamoxifen. Tamoxifen-resistant cells remained dependent on SEMA3C for growth and survival. Treatment with B1SP Fc fusion protein, a SEMA3C pathway inhibitor, attenuated SEMA3C-induced signaling and growth across a panel of tamoxifen sensitive and resistant ER⁺ breast cancer cells. Furthermore, SEMA3C silencing and B1SP treatment were associated with decreased EGFR signaling in TamR cells. Here, our study implicates SEMA3C in a functional role in ER⁺ breast cancer signaling and growth that suggests ER⁺ BCa patients may benefit from SEMA3C-targeted therapy. Full article

We previously reported on the experimental validation of several in silico-predicted glioma biomarkers (e.g., Plexin-B2 (PLXNB2), SLIT3, and Spondin-1 (SPON1)) that were found to be higher in human high-grade gliomas (HGGs). In this study, we validated their therapeutic potential by investigating antibody therapies against these three biomarkers in a preclinical mouse GL261 high-grade glioma model. Efficacies for antibody therapies against these biomarkers were assessed by survival and tumor volumes, biomarker expressions, cell invasion and proliferation, and bioinformatics gene/protein associations. Antibodies against PLXNB2, SLIT3, or SPON1 were effective in significantly reducing tumor volumes and increasing animal survival. With immunohistochemistry (IHC), these biomarkers were highly expressed in human HGGs, as well as in mice tumors. From IHC, CD44v6 was significantly decreased for all three antibody treatments, compared to UT GL261 tumors. Bioinformatics suggested that targeting either PLXNB2 or SPON1 may have a major effect on HGG cell migration and invasion (validated with CD44v6 IHC), whereas targeting SLIT3, in addition to affecting cell invasion, may also affect cell proliferation (not validated with Ki67 IHC). These results indicate that targeting these three biomarkers could add to the therapeutic arsenal against high-grade gliomas and that antibodies against them could be considered for clinical translation. Full article

The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, has no established function. The MET PSI sequence contains two CXXC motifs, usually found in protein disulfide isomerases (PDI). Using a scrambled oxidized RNAse enzymatic activity assay in vitro, we show, for the first time, that the MET extracellular domain displays disulfide isomerase activity, abolished by PSI domain antibodies. PSI domain deletion or mutations of CXXC sites to AXXA or SXXS result in a significant impairment of the cleavage of the MET 175 kDa precursor protein, abolishing the maturation of α and β chains, of, respectively, 50 kDa and 145 kDa, disulfide-linked. The uncleaved precursor is stuck in the Golgi apparatus and, interestingly, is constitutively phosphorylated. However, no signal transduction is observed as measured by AKT and MAPK phosphorylation. Consequently, biological responses to the MET ligand—hepatocyte growth factor (HGF)—such as growth and epithelial to mesenchymal transition, are hampered. These data show that the MET PSI domain is functional and is required for the maturation, surface expression, and biological functions of the MET oncogenic protein. Full article

Chronic pain is a debilitating condition that influences the social, economic, and psychological aspects of patients’ lives. Hence, the need for better treatment is drawing extensive interest from the research community. Developmental molecules such as Wnt, ephrins, and semaphorins are acknowledged as central players in the proper growth of a biological system. Their receptors and ligands are expressed in a wide variety in both neurons and glial cells, which are implicated in pain development, maintenance, and resolution. Thereby, it is not surprising that the impairment of those pathways affects the activities and functions of the entire cell. Evidence indicates aberrant activation of their pathways in the nervous system in rodent models of chronic pain. In those conditions, Wnt, ephrin, and semaphorin signaling participate in enhancing neuronal excitability, peripheral sensitization, synaptic plasticity, and the production and release of inflammatory cytokines. This review summarizes the current knowledge on three main developmental pathways and their mechanisms linked with the pathogenesis and progression of pain, considering their impacts on neuronal and glial cells in experimental animal models. Elucidations of the downstream pathways may provide a new mechanism for the involvement of Wnt, ephrin, and semaphorin pathways in pain chronicity. Full article