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Plant Physiology Dec 2023Mitogen-activated protein kinase (MAPK/MPK) cascades are key signaling modules that regulate plant immunity. ENHANCED DISEASE RESISTANCE1 (EDR1) encodes a Raf-like MAPK...
Mitogen-activated protein kinase (MAPK/MPK) cascades are key signaling modules that regulate plant immunity. ENHANCED DISEASE RESISTANCE1 (EDR1) encodes a Raf-like MAPK kinase kinase (MAPKKK) that negatively regulates plant defense in Arabidopsis (Arabidopsis thaliana). The enhanced resistance of edr1 requires MAPK KINASE4 (MKK4), MKK5, and MPK3. Although the edr1 mutant displays higher MPK3/6 activation, the mechanism by which plants increase MAPK cascade activation remains elusive. Our previous study showed that MAPKKK5 is phosphorylated at the Ser-90 residue in edr1 mutants. In this study, we demonstrated that the enhanced disease resistance of edr1 required MAPKKK5. Phospho-dead MAPKKK5S90A partially impaired the resistance of edr1, and the expression of phospho-mimetic MAPKKK5S90D in mapkkk5-2 resulted in enhanced resistance to the powdery mildew Golovinomyces cichoracearum strain UCSC1 and the bacterial pathogen Pseudomonas syringae pv. tomato (Pto) strain DC3000. Thus, Ser-90 phosphorylation in MAPKKK5 appears to play a crucial role in disease resistance. However, MAPKKK5-triggered cell death was not suppressed by EDR1. Furthermore, activated MPK3 phosphorylated the N terminus of MAPKKK5, and Ser-90 was one of the phosphorylated sites. Ser-90 phosphorylation increased MAPKKK5 stability, and EDR1 might negatively regulate MAPK cascade activation by suppressing the MPK3-mediated feedback regulation of MAPKKK5. Taken together, these results indicate that MPK3 phosphorylates MAPKKK5 to enhance MAPK cascade activation and disease resistance in edr1 mutants.
Topics: Humans; Disease Resistance; Arabidopsis Proteins; MAP Kinase Kinase Kinase 5; Mitogens; Arabidopsis; Gene Expression Regulation, Plant; Plant Diseases
PubMed: 37638889
DOI: 10.1093/plphys/kiad472 -
Journal of Cellular and Molecular... Feb 2022Fibroblast growth factor 8 (FGF-8), also known as androgen-induced growth factor (AIGF), is presumed to be a potent mitogenic cytokine that plays important roles in... (Review)
Review
Fibroblast growth factor 8 (FGF-8), also known as androgen-induced growth factor (AIGF), is presumed to be a potent mitogenic cytokine that plays important roles in early embryonic development, brain formation and limb development. In the bone environment, FGF-8 produced or received by chondrocyte precursor cells binds to fibroblast growth factor receptor (FGFR), causing different levels of activation of downstream signalling pathways, such as phospholipase C gamma (PLCγ)/Ca , RAS/mitogen-activated protein kinase-extracellular regulated protein kinases (RAS/MAPK-MEK-ERK), and Wnt-β-catenin-Axin2 signalling, and ultimately controlling chondrocyte proliferation, differentiation, cell survival and migration. However, the molecular mechanism of FGF-8 in normal or pathological cartilage remains unclear, and thus, FGF-8 represents a novel exploratory target for studies of chondrocyte development and cartilage disease progression. In this review, studies assessing the relationship between FGF-8 and chondrocytes that have been published in the past 5 years are systematically summarized to determine the probable mechanism and physiological effect of FGF-8 on chondrocytes. Based on the existing research results, a therapeutic regimen targeting FGF-8 is proposed to explore the possibility of treating chondrocyte-related diseases.
Topics: Cartilage; Cells, Cultured; Chondrocytes; Chondrogenesis; Fibroblast Growth Factor 8; Fibroblast Growth Factors; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor
PubMed: 35001536
DOI: 10.1111/jcmm.17174 -
Biochemical Society Transactions Feb 2021The RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade is aberrantly activated in a diverse set of human cancers and the RASopathy group of genetic... (Review)
Review
The RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade is aberrantly activated in a diverse set of human cancers and the RASopathy group of genetic developmental disorders. This protein kinase cascade is one of the most intensely studied cellular signaling networks and has been frequently targeted by the pharmaceutical industry, with more than 30 inhibitors either approved or under clinical evaluation. The ERK-MAPK cascade was originally depicted as a serial and linear, unidirectional pathway that relays extracellular signals, such as mitogenic stimuli, through the cytoplasm to the nucleus. However, we now appreciate that this three-tiered protein kinase cascade is a central core of a complex network with dynamic signaling inputs and outputs and autoregulatory loops. Despite our considerable advances in understanding the ERK-MAPK network, the ability of cancer cells to adapt to the inhibition of key nodes reveals a level of complexity that remains to be fully understood. In this review, we summarize important developments in our understanding of the ERK-MAPK network and identify unresolved issues for ongoing and future study.
Topics: Animals; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Neoplasms; Protein Interaction Maps; ras Proteins
PubMed: 33544118
DOI: 10.1042/BST20200507 -
Veterinary World Jun 2022The reports from the Ministry of Agriculture and Fisheries suggest that camels suffer less compared to goats, sheep, and cows from a number of common infectious diseases...
BACKGROUND AND AIM
The reports from the Ministry of Agriculture and Fisheries suggest that camels suffer less compared to goats, sheep, and cows from a number of common infectious diseases in Oman. However, there is no immunological evidence to substantiate this claim. This present study is, therefore, an attempt to study the immunological responses of camels, goats, sheep, and cows by comparing their oxidative respiratory burst of peripheral blood leukocytes (PBLs) as a marker of innate immunity occurring during phagocytosis and the mitogenic responses of their peripheral blood mononuclear leukocytes (PBMLs) as a marker of their adaptive immune response.
MATERIALS AND METHODS
Ten female adult animals (n = 10) were selected from each species (goats, sheep, and cows). The goats, sheep, and cows were maintained at the Agricultural Experiment Station, while camels were kept at the Royal Camel Corps (RCC). Blood samples were collected from the jugular vein in 7 mL of heparin and ethylenediaminetetraacetic acid vacutainer tubes. The oxidative respiratory burst of PBLs was measured using a chemiluminescence (CL) assay. Reactants consisted of 75 mL of whole blood diluted (1:50), 75 mL of luminol/isoluminol, and 75 mL of zymosan opsonized with non-heat inactivated serum/heat-inactivated serum or non-opsonized zymosan. CL responses were measured as relative light units and expressed as the mean count per minute and peak CL values. The mitogenic response of PBMLs to concanavalin A (Con-A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM) was tested using a WST-8 assay and read spectrophotometrically at 450 nm.
RESULTS
The present findings showed that camel PBLs generate significantly higher CL responses, both intracellularly as well as extracellularly, with zymosan opsonized with autologous serum. Camel PBLs demonstrated a significantly higher (p = 0.001) response when stimulated with zymosan opsonized with heat-inactivated serum compared to those of goat, sheep, and cow lymphocytes from camels exhibited significantly higher (p = 0.001) stimulation indices (SI) with Con-A, PHA, and PWM.
CONCLUSION
The present study suggests that camels are capable of mounting both superior innate as well as adaptive immune responses and provide immunological evidence supporting the belief of some authors, who have proposed that camels are less susceptible to a number of common infectious diseases than other domesticated ruminants.
PubMed: 35993061
DOI: 10.14202/vetworld.2022.1398-1407 -
Journal of Comparative Physiology. B,... Nov 2022Annual rhythms are observed in many physiological processes and are an important approach to cope with seasonal stressors. The use of lower vertebrates as an...
Annual rhythms are observed in many physiological processes and are an important approach to cope with seasonal stressors. The use of lower vertebrates as an experimental model is crucial to understand the evolution of this biological clock. This study aims to characterize the seasonal variability in the leukocyte immune responses in Channa punctatus. Leukocytes were harvested from peripheral blood and respiratory burst activity, leukocyte phagocytosis, and nitrite production were assessed to study innate immunity. Peripheral blood lymphocytes were segregated by centrifugation (density gradient) and proliferative responses of lymphocytes, in the presence of mitogens, were used to study cell-mediated immunity. Annual rhythms were validated in superoxide anion production, nitrite release and phagocytosis. Cosinor analysis revealed a differential pattern of lymphocyte proliferation which was dependent upon season and mitogen used. It was concluded that seasonal variation in immune activity might be associated with annual adaptation against diseases and the optimum immune status of seasonal breeders like fish helps them fight seasonal changes.
Topics: Animals; Fishes; Fresh Water; Leukocytes; Mitogens; Nitrites; Seasons; Superoxides
PubMed: 36053305
DOI: 10.1007/s00360-022-01460-7 -
Science Signaling Feb 2024More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current...
More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current generation of AKT inhibitors could be improved. Here, we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-dependent phenotypes in breast cancer cell lines. A growth inhibition screen with 288 cancer cell lines confirmed that INY-05-040 had a substantially higher potency than our first-generation AKT degrader (INY-03-041), with both compounds outperforming catalytic AKT inhibition by GDC-0068. Using multiomic profiling and causal network integration in breast cancer cells, we demonstrated that the enhanced efficacy of INY-05-040 was associated with sustained suppression of AKT signaling, which was followed by induction of the stress mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low basal JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Together, our study presents a framework for mapping the network-wide signaling effects of therapeutically relevant compounds and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling.
Topics: Humans; Female; Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Breast Neoplasms; Apoptosis; Mitogens; Multiomics; Proteomics; p38 Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase Kinases; JNK Mitogen-Activated Protein Kinases
PubMed: 38412255
DOI: 10.1126/scisignal.adf2670 -
World Journal of Gastroenterology Dec 2022Immune cells, including neutrophils, natural killer (NK) cells, T cells, NKT cells and macrophages, participate in the progression of acute liver injury and hepatic...
BACKGROUND
Immune cells, including neutrophils, natural killer (NK) cells, T cells, NKT cells and macrophages, participate in the progression of acute liver injury and hepatic recovery. To date, there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery.
AIM
To investigate the infiltration changes of various immune cells in acute liver injury models over time, and to study the relationship between the changes in leukocyte cell-derived chemotaxin 2 (LECT2) and the infiltration of several immune cells.
METHODS
Carbon tetrachloride- and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively. The quantitative changes in various immune cells were monitored at different time points. Serum samples were collected, and liver tissues were harvested. Ly6G, CD161, CD4, CD8 and F4/80 staining were used to indicate neutrophils, NK/NKT cells, CD4 T cells, CD8 T cells and macrophages, respectively. Lect2-KO mice were used to detect the function of LECT2.
RESULTS
During the injury and repair process, different types of immune cells began to increase, reached their peaks and fell into decline at different time points. Furthermore, when the serum alanine transaminase (ALT) and aspartate transaminase (AST) indices reverted to normal levels 7 d after the injury, the infiltration of immune cells still existed even 14 d after the injury, showing an obvious lag effect. We found that the expression of LECT2 was upregulated in acute liver injury mouse models, and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice. Compared with wild-type mice, Lect2-KO mice had different immune cell infiltration.
CONCLUSION
The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair. LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Concanavalin A; Killer Cells, Natural; Liver; Mice, Inbred C57BL; Neutrophils; Chemical and Drug Induced Liver Injury; Hepatitis, Autoimmune
PubMed: 36569272
DOI: 10.3748/wjg.v28.i46.6537 -
Frontiers in Endocrinology 2022Thyroid hormones, T (triiodothyronine) and T (thyroxine), induce a variety of long-term effects on important physiological functions, ranging from development and growth... (Review)
Review
Thyroid hormones, T (triiodothyronine) and T (thyroxine), induce a variety of long-term effects on important physiological functions, ranging from development and growth to metabolism regulation, by interacting with specific nuclear or cytosolic receptors. Extranuclear or nongenomic effects of thyroid hormones are mediated by plasma membrane or cytoplasmic receptors, mainly by αvβ3 integrin, and are independent of protein synthesis. A wide variety of nongenomic effects have now been recognized to be elicited through the binding of thyroid hormones to this receptor, which is mainly involved in angiogenesis, as well as in cell cancer proliferation. Several signal transduction pathways are modulated by thyroid hormone binding to αvβ3 integrin: protein kinase C, protein kinase A, Src, or mitogen-activated kinases. Thyroid hormone-activated nongenomic effects are also involved in the regulation of Na-dependent transport systems, such as glucose uptake, Na/K-ATPase, Na/H exchanger, and amino acid transport System A. Of note, the modulation of these transport systems is cell-type and developmental stage-dependent. In particular, dysregulation of Na/K-ATPase activity is involved in several pathological situations, from viral infection to cancer. Therefore, this transport system represents a promising pharmacological tool in these pathologies.
Topics: Adenosine Triphosphatases; Amino Acid Transport System A; Cyclic AMP-Dependent Protein Kinases; Glucose; Humans; Integrins; Mitogens; Neoplasms; Protein Kinase C; Thyroid Hormones; Thyroxine; Triiodothyronine
PubMed: 36213288
DOI: 10.3389/fendo.2022.961744 -
Current Cancer Drug Targets 2022The p38 MAP kinases are a sub-family of the broad group of mitogen-activated serinethreonine protein kinases. The best-characterised, most widely expressed, and most... (Review)
Review
The p38 MAP kinases are a sub-family of the broad group of mitogen-activated serinethreonine protein kinases. The best-characterised, most widely expressed, and most targeted by drugs is p38α MAP kinase. This review briefly summarises the place of p38α MAP kinase in cellular signalling and discusses the structures and activity profiles of representative examples of the major classes of inhibitors and activators (both synthetic compounds and natural products) of this enzyme. Primary screening was direct in vitro inhibition of isolated p38α enzyme.
Topics: Enzyme Inhibitors; Humans; Inflammation; Mitogen-Activated Protein Kinase 14; Mitogen-Activated Protein Kinase Kinases; Mitogens; Neoplasms; Phosphorylation; p38 Mitogen-Activated Protein Kinases
PubMed: 35168519
DOI: 10.2174/1568009622666220215142837 -
The Journal of Cell Biology Nov 2022Fibroblast growth factor (FGF2) is a potent mitogen that is secreted through an unconventional secretory pathway by crossing the plasma membrane directly. In this...
Fibroblast growth factor (FGF2) is a potent mitogen that is secreted through an unconventional secretory pathway by crossing the plasma membrane directly. In this current issue, Lolicato et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202106123) find that the secretion process is promoted by cholesterol, which enhances PI(4,5)P2 accessibility to FGF2 binding and alters membrane property to increase FGF2 translocation.
Topics: Cell Membrane; Cholesterol; Fibroblast Growth Factor 2; Mitogens; Secretory Pathway
PubMed: 36255389
DOI: 10.1083/jcb.202210007