C-type lectin 4 of Toxocara canis activates NF-ĸB and MAPK pathways by modulating NOD1/2 and RIP2 in murine macrophages in vitro.

Toxocara canis is a parasitic zoonose that is distributed worldwide and is one of the two pathogens causing toxocariasis. After infection, it causes serious public health and safety problems, which pose significant veterinary and medical challenges. To better understand the regulatory effects of T. canis infection on the host immune cells, murine macrophages (RAW264.7) were incubated with recombinant T. canis C-type lectin 4 (rTc-CTL-4) protein in vitro. The quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to analyze the nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2), receptor-interacting protein 2 (RIP2), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and mitogen-activated protein kinase (MAPK) on mRNA level and protein expression level in macrophages. Our results indicated that 10 µg/mL rTc-CTL-4 protein could modulate the expression of NOD1, NOD2, and RIP2 at both the transcriptional and translational levels. The protein translation levels of NF-κB, P-p65, p38, and P-p38 in macrophages were also modulated by rTc-CTL-4 protein. Macrophages were co-incubated with rTc-CTL-4 protein after siRNA silencing of NOD1, NOD2, and RIP2. The expression levels of NF-κB, P-p65, p38, and P-p38 were significantly changed compared with the negative control groups (Neg. Ctrl.). Taken together, rTc-CTL-4 protein seemed to act on NOD1/2-RIP2-NF-κB and MAPK signaling pathways in macrophages and might activate MAPK and NF-κB signaling pathways by regulating NOD1, NOD2, and RIP2. The insights from the above studies could contribute to our understanding of immune recognition and regulatory mechanisms of T. canis infection in the host animals.

Extracranial Vascular Anomalies Driven by RAS/MAPK Variants: Spectrum and Genotype-Phenotype Correlations.

BACKGROUND: We aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen-activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification. METHODS AND RESULTS: This retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen-activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies. PVs were detected by the targeted sequencing of panels of genes known to be associated with vascular anomalies, performed using DNA from affected tissue. Subgroup analyses were performed according to the affected genes with regard to phenotypic characteristics in a descriptive manner. Twenty-five vascular malformations, 3 vascular tumors, and 1 patient with both a vascular malformation and vascular tumor presented the following distribution of PVs in genes: Kirsten rat sarcoma viral oncogene (n=10), neuroblastoma ras viral oncogene homolog (n=1), Harvey rat sarcoma viral oncogene homolog (n=5), V-Raf murine sarcoma viral oncogene homolog B (n=8), and mitogen-activated protein kinase kinase 1 (n=5). Patients with RAS PVs had advanced disease stages according to the Schobinger classification (stage 3-4: RAS, 9/13 versus non-RAS, 3/11) and more frequent progression after treatment (RAS, 10/13 versus non-RAS, 2/11). Lesions with Kirsten rat sarcoma viral oncogene PVs infiltrated more tissue layers compared with the other PVs including other RAS PVs (multiple tissue layers: Kirsten rat sarcoma viral oncogene, 8/10 versus other PVs, 6/19). CONCLUSIONS: This comparison of patients with various PVs in genes of the RAS/MAPK pathway provides potential associations with certain morphological and clinical phenotypes. RAS variants were associated with more aggressive phenotypes, generating preliminary data and hypothesis for future larger studies.

Comprehensive analysis of MAPK gene family in upland cotton (Gossypium hirsutum) and functional characterization of GhMPK31 in regulating defense response to insect infestation.

KEY MESSAGE: The transcriptomic, phenotypic and metabolomic analysis of transgenic plants overexpressing GhMPK31 in upland cotton revealed the regulation of H2O2 burst and the synthesis of defensive metabolites by GhMPK31. Mitogen-activated protein kinases (MAPKs) are a crucial class of protein kinases, which play an essential role in various biological processes in plants. Upland cotton (G. hirsutum) is the most widely cultivated cotton species with high economic value. To gain a better understanding of the role of the MAPK gene family, we conducted a comprehensive analysis of the MAPK gene family in cotton. In this study, a total of 55 GhMPK genes were identified from the whole genome of G. hirsutum. Through an investigation of the expression patterns under diverse stress conditions, we discovered that the majority of GhMPK family members demonstrated robust responses to abiotic stress, pathogen stress and pest stress. Furthermore, the overexpression of GhMPK31 in cotton leaves led to a hypersensitive response (HR)-like cell death phenotype and impaired the defense capability of cotton against herbivorous insects. Transcriptome and metabolomics data analysis showed that overexpression of GhMPK31 enhanced the expression of H2O2-related genes and reduced the accumulation of defensive related metabolites. The direct evidence of GhMPK31 interacting with GhRBOHB (H2O2-generating protein) were found by Y2H, BiFC, and LCI. Therefore, we propose that the increase of H2O2 content caused by overexpression of GhMPK31 resulted in HR-like cell death in cotton leaves while reducing the accumulation of defensive metabolites, ultimately leading to a decrease in the defense ability of cotton against herbivorous insects. This study provides valuable insights into the function of MAPK genes in plant resistance to herbivorous insects.

Tomato SlMAPK3 Modulates Cold Resistance by Regulating the Synthesis of Raffinose and the Expression of SlWRKY46.

Mitogen-activated protein kinase (MAPK) cascades and raffinose have been observed to increase in plants exposed to cold. However, it remains elusive whether and how MAPK regulates raffinose synthesis under cold stress. Here, overexpression of SlMAPK3 promoted the accumulation of galactinol and raffinose under cold stress, while CRISPR/Cas9-mediated mutants showed the opposite results. Moreover, SlMAPK3 promoted the expression of SlWRKY46 at low temperatures and interacted with SlWRKY46 protein. Overexpression of SlWRKY46 enhanced cold resistance. Furthermore, SlWRKY46 directly bound to the promoter of SlGols1 to enhance its expression and promoted the accumulation of raffinose. Virus-induced gene-silencing (VIGS)-mediated knockdown of SlGols1 remarkably elevated cold sensitivity and reduced raffinose content. Meanwhile, exogenous supplementation of raffinose could improve the cold tolerance of tomato plants. Thus, our data indicates that SlMAPK3 modulates cold resistance by regulating raffinose content and SlWRKY46 expression. SlWRKY46 also promotes the accumulation of raffinose by inducing the expression of SlGols1.

Role of Pmk1, Mpk1, or Hog1 in the mitogen-activated protein kinase pathway of Aspergillus cristatus.

Aspergillus cristatus is a probiotic fungus known for its safety and abundant secondary metabolites, making it a promising candidate for various applications. However, limited progress has been made in researching A. cristatus due to challenges in genetic manipulation. The mitogen-activated protein kinase (MAPK) signaling pathway is involved in numerous physiological processes, but its specific role in A. cristatus remains unclear. In this study, we successfully developed an efficient polyethylene glycol (PEG)-mediated protoplast transformation method for A. cristatus, enabling us to investigate the function of Pmk1, Mpk1, and Hog1 in the MAPK signaling pathway. Our findings revealed that Pmk1, Mpk1, and Hog1 are crucial for sexual reproduction, melanin synthesis, and response to external stress in A. cristatus. Notably, the deletion of Pmk1, Mpk1, or Hog1 resulted in the loss of sexual reproduction capability in A. cristatus. Overall, this research on MAPK will contribute to the continued understanding of the reproductive strategy and melanin synthesis mechanism of A. cristatus.

Mitogen-activated protein kinases MPK3 and MPK6 phosphorylate receptor-like cytoplasmic kinase CDL1 to regulate soybean basal immunity.

Soybean cyst nematode (SCN; Heterodera glycines Ichinohe), one of the most devastating soybean (Glycine max) pathogens, causes significant yield loss in soybean production. Nematode infection triggers plant defense responses; however, the components involved in the upstream signaling cascade remain largely unknown. In this study, we established that a mitogen-activated protein kinase (MAPK) signaling module, activated by nematode infection or wounding, is crucial for soybeans to establish SCN resistance. GmMPK3 and GmMPK6 directly interact with CDG1-LIKE1 (GmCDL1), a member of the receptor-like cytoplasmic kinase (RLCK) subfamily VII. These kinases phosphorylate GmCDL1 at Thr-372 to prevent its proteasome-mediated degradation. Functional analysis demonstrated that GmCDL1 positively regulates immune responses and promotes SCN resistance in soybeans. GmMPK3-mediated and GmMPK6-mediated phosphorylation of GmCDL1 enhances GmMPK3 and GmMPK6 activation and soybean disease resistance, representing a positive feedback mechanism. Additionally, 2 L-type lectin receptor kinases, GmLecRK02g and GmLecRK08g, associate with GmCDL1 to initiate downstream immune signaling. Notably, our study also unveils the potential involvement of GmLecRKs and GmCDL1 in countering other soybean pathogens beyond nematodes. Taken together, our findings reveal the pivotal role of the GmLecRKs-GmCDL1-MAPK regulatory module in triggering soybean basal immune responses.

The role of silymarin and MAPK pathway in the regulation of proliferation and invasion of non-small cell lung cancer cells.

We aimed to explore the role of silymarin and mitogen-activated protein kinase (MAPK) pathway in the regulation of proliferation and invasion of non-small cell lung cancer cells. Non-small cell lung cancer cells were cultured and divided into groups and treated with drugs, and A blank control group was set up. The concentration of silymarin in the experimental group was 10 mg/L, 20 mg/L and 40 mg/L, respectively, which were recorded as groups A, B and C, and three repeated experiments were performed in each group. Absorbance (A value), survival rate and number of invasions were measured at 490 nm 24 h and 48 h after treatment, and the protein expression levels of MMP-2, MMP-9, p-p38, p-JNK and p-ERK 1/2 of cells in each group were detected. There were differences in the A value (control group > Group A > Group B > Group C), cell survival rate (control group < group A < group B < group C) and the number of cell invasions (control group > Group A > Group B > group C) at 24h and 48h among all groups (P<0.05). After 24h of administration, the mRNA expression of MMP-2 and MMP-9, P-P38 and P-JNK protein expression were significantly different among groups, and the control group was > group A > Group B > group C (P<0.05). There were no significant differences in protein expression levels of p38, JNK, ERK 1/2 and P-ERK 1/2 among all groups (P>0.05). Silymarin may inhibit the proliferation and invasion of non-small cell lung cancer cells by inhibiting the activity of MAPK pathway, and the higher the concentration, the more obvious the inhibition effect, which provides a basis for further research and treatment of non-small cell lung cancer.

Aspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection.

Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage. Here, we show that GliT:GFP and GtmA:GFP are localized in the cytoplasm and in vacuoles during GT production. The Mitogen-Activated Protein kinase MpkA is essential for GT production and self-protection, interacts physically with GliT and GtmA and it is necessary for their regulation and subsequent presence in the vacuoles. The sensor histidine kinase SlnASln1 is important for modulation of MpkA phosphorylation. Our work emphasizes the importance of MpkA and compartmentalization of cellular events for GT production and self-defense.

Heat stress-induced activation of MAPK pathway attenuates Atf1-dependent epigenetic inheritance of heterochromatin in fission yeast.

Eukaryotic cells are constantly exposed to various environmental stimuli. It remains largely unexplored how environmental cues bring about epigenetic fluctuations and affect heterochromatin stability. In the fission yeast Schizosaccharomyces pombe, heterochromatic silencing is quite stable at pericentromeres but unstable at the mating-type (mat) locus under chronic heat stress, although both loci are within the major constitutive heterochromatin regions. Here, we found that the compromised gene silencing at the mat locus at elevated temperature is linked to the phosphorylation status of Atf1, a member of the ATF/CREB superfamily. Constitutive activation of mitogen-activated protein kinase (MAPK) signaling disrupts epigenetic maintenance of heterochromatin at the mat locus even under normal temperature. Mechanistically, phosphorylation of Atf1 impairs its interaction with heterochromatin protein Swi6HP1, resulting in lower site-specific Swi6HP1 enrichment. Expression of non-phosphorylatable Atf1, tethering Swi6HP1 to the mat3M-flanking site or absence of the anti-silencing factor Epe1 can largely or partially rescue heat stress-induced defective heterochromatic maintenance at the mat locus.

Activation of MAPK-mediated immunity by phosphatidic acid in response to positive-strand RNA viruses.

Increasing evidence suggests that mitogen-activated protein kinase (MAPK) cascades play a crucial role in plant defense against viruses. However, the mechanisms that underlie the activation of MAPK cascades in response to viral infection remain unclear. In this study, we discovered that phosphatidic acid (PA) represents a major class of lipids that respond to Potato virus Y (PVY) at an early stage of infection. We identified NbPLDα1 (Nicotiana benthamiana phospholipase Dα1) as the key enzyme responsible for increased PA levels during PVY infection and found that it plays an antiviral role. 6K2 of PVY interacts with NbPLDα1, leading to elevated PA levels. In addition, NbPLDα1 and PA are recruited by 6K2 to membrane-bound viral replication complexes. On the other hand, 6K2 also induces activation of the MAPK pathway, dependent on its interaction with NbPLDα1 and the derived PA. PA binds to WIPK/SIPK/NTF4, prompting their phosphorylation of WRKY8. Notably, spraying with exogenous PA is sufficient to activate the MAPK pathway. Knockdown of the MEK2-WIPK/SIPK-WRKY8 cascade resulted in enhanced accumulation of PVY genomic RNA. 6K2 of Turnip mosaic virus and p33 of Tomato bushy stunt virus also interacted with NbPLDα1 and induced the activation of MAPK-mediated immunity. Loss of function of NbPLDα1 inhibited virus-induced activation of MAPK cascades and promoted viral RNA accumulation. Thus, activation of MAPK-mediated immunity by NbPLDα1-derived PA is a common strategy employed by hosts to counteract positive-strand RNA virus infection.

A MAP kinase cascade broadly regulates the lifestyle of Sclerotinia sclerotiorum and can be targeted by HIGS for disease control.

Sclerotinia sclerotiorum causes white mold or stem rot in a wide range of economically important plants, bringing significant yield losses worldwide. Control of this pathogen is difficult as its resting structure sclerotia can survive in soil for years, and no Resistance genes have been identified in S. sclerotiorum hosts. Host-induced gene silencing (HIGS) has shown promising effects in controlling many fungal pathogens, including S. sclerotiorum. However, better molecular genetic understanding of signaling pathways involved in its development and pathogenicity is needed to provide effective HIGS gene targets. Here, by employing a forward genetic screen, we characterized an evolutionarily conserved mitogen-activated protein kinase (MAPK) cascade in S. sclerotiorum, consisting of SsSte50-SsSte11-SsSte7-Smk1, which controls mycelial growth, sclerotia development, compound appressoria formation, virulence, and hyphal fusion. Moreover, disruption of the putative downstream transcription factor SsSte12 led to normal sclerotia but deformed appressoria and attenuated host penetration, as well as impaired apothecia formation, suggestive of diverged regulation downstream of the MAPK cascade. Most importantly, targeting SsSte50 using host-expressed double-stranded RNA resulted in largely reduced virulence of S. sclerotiorum on both Nicotiana benthamiana leaves and transgenic Arabidopsis thaliana plants. Therefore, this MAPK signaling cascade is generally needed for its growth, development, and pathogenesis and can serve as ideal HIGS targets for mitigating economic damages caused by S. sclerotiorum infection.

Dephosphorylation of the MAP kinases MPK6 and MPK3 fine-tunes responses to wounding and herbivory in Arabidopsis.

The Arabidopsis MAP Kinases (MAPKs) MPK6 and MPK3 and orthologs in other plants function as major stress signaling hubs. MAPKs are activated by phosphorylation and are negatively regulated by MAPK-inactivating phosphatases (MIPPs), which alter the intensity and duration of MAPK signaling via dephosphorylation. Unlike in other plant species, jasmonic acid (JA) accumulation in Arabidopsis is apparently not MPK6- and MPK3-dependent, so their role in JA-mediated defenses against herbivorous insects is unclear. Here we explore whether changes in MPK6/3 phosphorylation kinetics in Arabidopsis MIPP mutants lead to changes in hormone synthesis and resistance against herbivores. The MIPPs MKP1, DsPTP1, PP2C5, and AP2C1 have been implicated in responses to infection, drought, and osmotic stress, which all impinge on JA-mediated defenses. In loss-of-function mutants, we found that the four MIPPs alter wound-induced MPK6/3 phosphorylation kinetics and affect the accumulation of the defense hormones JA, abscisic acid, and salicylic acid, as compared to wild type plants (Col-0). Moreover, MPK6/3 misregulation in MIPP or MAPK mutant plants resulted in slight changes in the resistance to Trichoplusia ni and Spodoptera exigua larvae as compared to Col-0. Our data indicate that MPK6/3 and the four MIPPs moderately contribute to wound signaling and defense against herbivorous insects in Arabidopsis.

Phosphorylation of AGO1a by MAP kinases is required for miRNA mediated resistance against Xanthomonas oryzae pv. oryzae infection in rice.

Bacterial leaf blight is a devastating disease caused by Xanthomonas oryzae pv. oryzae (Xoo) which causes severe crop loss in rice. The molecular mechanism that initiates defense against such pathogens remains unexplored. Reports have suggested crucial role of several miRNAs in regulating immune responses in plants. Argonaute (AGO) proteins have been implicated in imparting immunity against pathogens by using small RNAs as guide molecules. Here, we show that phosphorylation of rice AGO1a by MAP kinases is required for miRNA expression regulation during Xoo infection. AGO1a is induced in response to pathogen infection and is under the control of SA signaling pathway. The pathogen responsive MAP kinases MPK3, MPK4 and MPK6, interact with AGO1a in planta and can phosphorylate the protein in vitro. Overexpression of AGO1a extends disease resistance against Xoo in rice and leads to a higher accumulation of miRNAs. Conversely, overexpression of a non phosphorylatable mutant protein aggravates disease susceptibility and remarkably suppresses the miRNA expression levels. At a molecular level, phosphorylation of AGO1a by MAP kinase is required for increased accumulation of miRNAs during pathogen challenge. Taken together, the data suggests that OsAGO1a is a direct phosphorylation target of MAP kinases and this phosphorylation is crucial for its role in imparting disease resistance.

Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes.

p38 Mitogen-Activated Protein Kinase (MAPK) cascades are central regulators of numerous physiological cellular processes, including stress response signaling. In C. elegans, mitochondrial dysfunction activates a PMK-3/p38 MAPK signaling pathway (MAPKmt), but its functional role still remains elusive. Here, we demonstrate the induction of MAPKmt in worms deficient in the lonp-1 gene, which encodes the worm ortholog of mammalian mitochondrial LonP1. This induction is subjected to negative regulation by the ATFS-1 transcription factor through the CREB-binding protein (CBP) ortholog CBP-3, indicating an interplay between both activated MAPKmt and mitochondrial Unfolded Protein Response (UPRmt) surveillance pathways. Our results also reveal a genetic interaction in lonp-1 mutants between PMK-3 kinase and the ZIP-2 transcription factor. ZIP-2 has an established role in innate immunity but can also modulate the lifespan by maintaining mitochondrial homeostasis during ageing. We show that in lonp-1 animals, ZIP-2 is activated in a PMK-3-dependent manner but does not confer increased survival to pathogenic bacteria. However, deletion of zip-2 or pmk-3 shortens the lifespan of lonp-1 mutants, suggesting a possible crosstalk under conditions of mitochondrial perturbation that influences the ageing process. Furthermore, loss of pmk-3 specifically diminished the extreme heat tolerance of lonp-1 worms, highlighting the crucial role of PMK-3 in the heat shock response upon mitochondrial LONP-1 inactivation.

Mycoparasitism related targets of Tmk1 indicate stimulating regulatory functions of this MAP kinase in Trichoderma atroviride.

Mycoparasitism is a key feature of Trichoderma (Hypocreales, Ascomycota) biocontrol agents. Recent studies of intracellular signal transduction pathways of the potent mycoparasite Trichoderma atroviride revealed the involvement of Tmk1, a mitogen-activated protein kinase (MAPK), in triggering the mycoparasitic response. We previously showed that mutants missing Tmk1 exhibit reduced mycoparasitic activity against several plant pathogenic fungi. In this study, we identified the most robustly regulated targets that were governed by Tmk1 during mycoparasitism using transcriptome and proteome profiling. Tmk1 mainly exerts a stimulating function for T. atroviride during its mycoparasitic interaction with the fungal plant pathogen Rhizoctonia solani, as reflected by 89% of strongly differently responding genes in the ∆tmk1 mutant compared to the wild type. Specifically, 54% of these genes showed strong downregulation in the response with a deletion of the tmk1 gene, whereas in the wild type the same genes were strongly upregulated during the interaction with the fungal host. These included the gene encoding the mycoparasitism-related proteinase Prb1; genes involved in signal transduction pathways such as a candidate coding for a conserved 14-3-3 protein, and a gene coding for Tmk2, the T. atroviride cell-wall integrity MAP kinase; genes encoding a specific siderophore synthetase, and multiple FAD-dependent oxidoreductases and aminotransferases. Due to the phosphorylating activity of Tmk1, different (phospho-)proteomics approaches were applied and identified proteins associated with cellular metabolism, energy production, protein synthesis and fate, and cell organization. Members of FAD- and NAD/NADP-binding-domain proteins, vesicular trafficking of molecules between cellular organelles, fungal translational, as well as protein folding apparatus were among others found to be phosphorylated by Tmk1 during mycoparasitism. Outstanding downregulation in the response of the ∆tmk1 mutant to the fungal host compared to the wild type at both the transcriptome and the proteome levels was observed for nitrilase, indicating that its defense and detoxification functions might be greatly dependent on Tmk1 during T. atroviride mycoparasitism. An intersection network analysis between the identified transcripts and proteins revealed a strong involvement of Tmk1 in molecular functions with GTPase and oxidoreductase activity. These data suggest that during T. atroviride mycoparasitism this MAPK mainly governs processes regulating cell responses to extracellular signals and those involved in reactive oxygen stress.

Langerhans cell histiocytosis: current advances in molecular pathogenesis.

Langerhans cell histiocytosis (LCH) is a rare and clinically heterogeneous hematological disease characterized by the accumulation of mononuclear phagocytes in various tissues and organs. LCH is often characterized by activating mutations of the mitogen-activated protein kinase (MAPK) pathway with BRAFV600E being the most recurrent mutation. Although this discovery has greatly helped in understanding the disease and in developing better investigational tools, the process of malignant transformation and the cell of origin are still not fully understood. In this review, we focus on the newest updates regarding the molecular pathogenesis of LCH and novel suggested pathways with treatment potential.

The SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis in prostate cancer.

Aberrant activation of Ras/Raf/mitogen-activated protein kinase (MAPK) signaling is frequently linked to metastatic prostate cancer (PCa); therefore, the characterization of modulators of this pathway is critical for defining therapeutic vulnerabilities for metastatic PCa. The lysine methyltransferase SET and MYND domain 3 (SMYD3) methylates MAPK kinase kinase 2 (MAP3K2) in some cancers, causing enhanced activation of MAPK signaling. In PCa, SMYD3 is frequently overexpressed and associated with disease severity; however, its molecular function in promoting tumorigenesis has not been defined. We demonstrate that SMYD3 critically regulates tumor-associated phenotypes via its methyltransferase activity in PCa cells and mouse xenograft models. SMYD3-dependent methylation of MAP3K2 promotes epithelial-mesenchymal transition associated behaviors by altering the abundance of the intermediate filament vimentin. Furthermore, activation of the SMYD3-MAP3K2 signaling axis supports a positive feedback loop continually promoting high levels of SMYD3. Our data provide insight into signaling pathways involved in metastatic PCa and enhance understanding of mechanistic functions for SMYD3 to reveal potential therapeutic opportunities for PCa.

PKD1 participates in the processing of aortic dissection via regulating vascular smooth muscle cell contraction and MAPK signaling.

Aortic Dissection (AD) is a cardiovascular emergency with high mortality, of which one feature is the phenotypic switch of vascular smooth muscle cells (VSMCs). Transient Receptor Potential Channel Interacting (PKD1) has been regarded as one regulator as well as one biomarker for AD. However, multiple candidate pathways were reported though which PKD1 regulates AD in previous study, a comprehensive insight is still absent. In this study, we compared the AD and normal samples in transcriptome scale, and detected 717 PKD1-related differential expressed genes, which enriched in mitogen-activated protein kinase (MAPK) signal transduction (AD tissue preference) and VSMC contraction pathway (normal tissue preference). Furthermore, we also found two important functional hub genes in PKD1 regulation, JUN and ACTN2, and established a carnal-miRNA-mRNA network. Our study demonstrated the co-regulation of muscle development and signal transduction in AD's progression, and also provided the genetic basis for the following mechanism research with AD.

Mitogen-activated protein kinase (MAPK) cascades-A yeast perspective.

Discovery of the class of protein kinase now dubbed a mitogen (or messenger)-activated protein kinase (MAPK) is an illustrative example of how disparate lines of investigation can converge and reveal an enzyme family universally conserved among eukaryotes, from single-celled microbes to humans. Moreover, elucidation of the circuitry controlling MAPK function defined a now overarching principle in enzyme regulation-the concept of an activation cascade mediated by sequential phosphorylation events. Particularly ground-breaking for this field of exploration were the contributions of genetic approaches conducted using several model organisms, but especially the budding yeast Saccharomyces cerevisiae. Notably, examination of how haploid yeast cells respond to their secreted peptide mating pheromones was crucial in pinpointing genes encoding MAPKs and their upstream activators. Fully contemporaneous biochemical analysis of the activities elicited upon stimulation of mammalian cells by insulin and other growth- and differentiation-inducing factors lead eventually to the demonstration that components homologous to those in yeast were involved. Continued studies of these pathways in yeast were integral to other foundational discoveries in MAPK signaling, including the roles of tethering, scaffolding and docking interactions.

MAPK signaling pathway-based glioma subtypes, machine-learning risk model, and key hub proteins identification.

An early diagnosis and precise prognosis are critical for the treatment of glioma. The mitogen­activated protein kinase (MAPK) signaling pathway potentially affects glioma, but the exploration of the clinical values of the pathway remains lacking. We accessed data from TCGA, GTEx, CGGA, etc. Up-regulated MAPK signaling pathway genes in glioma were identified and used to cluster the glioma subtypes using consensus clustering. The subtype differences in survival, cancer stemness, and the immune microenvironment were analyzed. A prognostic model was trained with the identified genes using the LASSO method and was validated with three external cohorts. The correlations between the risk model and cancer-associated signatures in cancer were analyzed. Key hub genes of the gene set were identified by hub gene analysis and survival analysis. 47% of the MAPK signaling pathway genes were overexpressed in glioma. Subtypes based on these genes were distinguished in survival, cancer stemness, and the immune microenvironment. A risk model was calculated with high confidence in the prediction of overall survival and was correlated with multiple cancer-associated signatures. 12 hub genes were identified and 8 of them were associated with survival. The MAPK signaling pathway was overexpressed in glioma with prognostic value.