Reciprocal Control of Osteogenic and Adipogenic Differentiation by ERK/MAP Kinase Phosphorylation of Runx2 and PPARγ Transcription Factors

LPS and MTP-PE (liposome-encapsulatedN-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-:[1',2'-dipalmitoyl-sni-glycero-3-(hydroxy-phosphoryl-oxyl)] etylamide) induce in liver macrophages a synthesis and release of TNF-α, nitric oxide and prostanoids. Both agents induce an expression of mRNA's encoding TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and of corresponding proteins. LPS and MTP-PE induce a rapid activation of the extracellular regulated kinase (ERK) isoenzymes-1 and -2. Inhibition of map kinase isoenzymes leads to a decreased release of TNF-α, nitric oxide and prostaglandin (PG) E2after both agents. The transcription factors NF-κB and AP-1 are strongly activated by LPS within 30 minutes. MTP-PE induces a weak activation of both transcription factors only after 5 hours. Inhibition of NF-κB inhibits the LPS- but not the MTP-PE-induced release of TNF-α, nitric oxide and PGE2. PGE2release after LPS is higher than after MTP-PE. Exogenously added PGE2inhibits the activation of map kinase and TNF-α release by LPS, but not by MTP-PE. Release of nitric oxide after LPS and MTP-PE is enhanced after prior addition of PGE2. PGD2is without any effect. MTP-PE, but not LPS, induces a cytotoxicity of Kupffer cells against P815 tumor target cells. The MTP-PE-induced cytotoxicity is reduced by TNF-α neutralizing antibodies, indicating the involvement of TNF-α. Thus our results suggest that the different potencies of LPS and MTP-PE as immunomodulators probably result from different actions on Kupffer cells, resulting in differences in the amounts and kinetics of released TNF-α and PGE2, and that PGE2plays an important regulatory role in the action of LPS, but not in the actions of MTP-PE.

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Altered MAP kinase phosphorylation and impaired motor coordination in PTPRR deficient mice

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2006.04398.x ◽

2006 ◽

Vol 101 (3) ◽

pp. 829-840 ◽

Cited By ~ 23

Author(s):

Renato G. S. Chirivi ◽

Yvet E. Noordman ◽

Catharina E. E. M. Van der Zee ◽

Wiljan J. A. J. Hendriks

Keyword(s):

Map Kinase ◽

Motor Coordination ◽

Kinase Phosphorylation ◽

Deficient Mice

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Platelet activation byStreptococcus sanguinisis accompanied by MAP kinase phosphorylation

Platelets ◽

10.3109/09537104.2012.661105 ◽

2012 ◽

Vol 24 (1) ◽

pp. 6-14 ◽

Cited By ~ 4

Author(s):

Ahmed Y. Abdulrehman ◽

Elke C. G. Jackson ◽

Archibald McNicol

Keyword(s):

Map Kinase ◽

Platelet Activation ◽

Kinase Phosphorylation

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Functional Role of p38 Mitogen Activated Protein Kinase in Platelet Activation induced by a Thromboxane A2 Analogue and by 8-iso-prostaglandin F2 α

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613101 ◽

2002 ◽

Vol 87 (05) ◽

pp. 888-898 ◽

Cited By ~ 23

Author(s):

Stefania Gaino ◽

Valeria Zuliani ◽

Rosa Tommasoli ◽

Donatella Benati ◽

Riccardo Ortolani ◽

...

Keyword(s):

Map Kinase ◽

Platelet Activation ◽

Tyrosine Kinases ◽

Actin Polymerization ◽

Shape Change ◽

Specific Inhibitor ◽

P38 Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Kinase Phosphorylation

SummaryWe investigated similarities in the signaling pathways elicited by the F2 isoprostane 8-iso-PGF2α and by low doses of U46619 to induce platelet activation. Both 0.01-0.1 µmol/L U46619 and 0.01-1 µmol/L 8-isoPGF2α triggered shape change and filopodia extension, as well as adhesion to immobilized fibrinogen of washed platelets. At these doses the two platelet agonists failed to trigger secretion and aggregation, which were however induced by higher doses of U46619 (0.1-1 µmol/L). SB203580 (1-10 µmol/L), a specific inhibitor of the p38 mitogen activated protein (MAP) kinase blunted platelet shape change and adhesion induced by 0.05-1 µmol/L 8-iso-PGF2α and by 0.01 µmol/L U46619. These platelet responses were also inhibited by 20 µmol/L cytochalasin D, an inhibitor of actin polymerization, and 50 µmol/L piceatannol, an inhibitor of the Syk tyrosine kinases. Both 8-iso-PGF2α and U46619-induced p38 MAP kinase phosphorylation in suspended platelets and this was inhibited by piceatannol, indicating that Syk activation occurs upstream p38 MAP kinase phosphorylation. These findings suggest that the signaling pathway triggered by both 8-iso-PGF2α and low concentrations of U46619 to induce platelet adhesion and shape change implicates Syk, the p38 MAP kinase, and actin polymerization.

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Insulin Induces Heterologous Desensitization of G Protein-Coupled Receptor and Insulin-Like Growth Factor I Signaling by Downregulating β-Arrestin-1

Molecular and Cellular Biology ◽

10.1128/mcb.22.17.6272-6285.2002 ◽

2002 ◽

Vol 22 (17) ◽

pp. 6272-6285 ◽

Cited By ~ 60

Author(s):

Stéphane Dalle ◽

Takeshi Imamura ◽

David W. Rose ◽

Dorothy Sears Worrall ◽

Satoshi Ugi ◽

...

Keyword(s):

Growth Factor ◽

Map Kinase ◽

Insulin Treatment ◽

Ectopic Expression ◽

Wild Type ◽

Factor I ◽

Igf I ◽

Heterologous Desensitization ◽

Kinase Phosphorylation ◽

G Protein Coupled

ABSTRACT β-Arrestin-1 mediates agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCRs) and is also essential for GPCR mitogenic signaling. In addition, insulin-like growth factor I receptor (IGF-IR) endocytosis is facilitated by β-arrestin-1, and internalization is necessary for IGF-I-stimulated mitogen-activated protein (MAP) kinase activation. Here, we report that treatment of cells for 12 h with insulin (100 ng/ml) induces an ∼50% decrease in cellular β-arrestin-1 content due to ubiquitination of β-arrestin-1 and proteosome-mediated degradation. This insulin-induced decrease in β-arrestin-1 content was blocked by inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with wortmannin and PD98059, respectively. We also found a marked decrease in the association of β-arrestin-1 with the IGF-IR and a 55% inhibition of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated, β-arrestin-1-downregulated cells, there was complete inhibition of lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase phosphorylation. This was associated with a decrease in β-arrestin-1 association with the β2-AR as well as a decrease in β-arrestin-1-Src and Src-β2-AR association. Ectopic expression of wild-type β-arrestin-1 in insulin-treated cells in which endogenous β-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. In conclusion, we found the following. (i) Chronic insulin treatment leads to enhanced β-arrestin-1 degradation. (ii) This downregulation of endogenous β-arrestin-1 is associated with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling, which can be rescued by ectopic expression of wild-type β-arrestin-1. (iii) Finally, these results describe a novel mechanism for heterologous desensitization, whereby insulin treatment can impair GPCR signaling, and highlight the importance of β-arrestin-1 as a target molecule for this desensitization mechanism.

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Positive feedback induces switch between distributive and processive phosphorylation of Hog1

10.1101/2020.05.05.078352 ◽

2020 ◽

Author(s):

Maximilian Mosbacher ◽

Sung Sik Lee ◽

Matthias Peter ◽

Manfred Claassen

Keyword(s):

Map Kinase ◽

Positive Feedback ◽

Ode Models ◽

Cellular Decision Making ◽

Activation Data ◽

Best Fitting ◽

Phosphorylation Mechanism ◽

Kinase Phosphorylation ◽

Multiple Conditions

SummaryCellular decision making often builds on ultrasensitive MAPK pathways. The phosphorylation mechanism of MAP kinase has so far been described as either distributive or processive, with distributive mechanisms generating ultrasensitivity in theoretical analyses. However, the in vivo mechanism of MAP kinase phosphorylation and its regulation by feedback loops remain unclear. We thus characterized the regulation of the MAP kinase Hog1 in Saccharomyces cerevisiae, which is transiently activated in response to hyperosmolarity. Specifically, we combined Hog1 activation data from different modalities and multiple conditions. We constructed ODE models with different pathway topologies, which were then assessed via parameter estimation and model selection. Interestingly, our best fitting model switches between distributive and processive phosphorylation behavior via a positive feedback loop targeting the MAP kinase-kinase Pbs2. Simulations further suggest that this mixed mechanism is required not only for full sensitivity to stimuli, but also to ensure robustness to different perturbations.

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Epidermal growth factor and Ras regulate gene expression in GH4 pituitary cells by separate, antagonistic signal transduction pathways.

Molecular and Cellular Biology ◽

10.1128/mcb.15.12.6777 ◽

1995 ◽

Vol 15 (12) ◽

pp. 6777-6784 ◽

Cited By ~ 15

Author(s):

C A Pickett ◽

A Gutierrez-Hartmann

Keyword(s):

Signal Transduction ◽

Transcription Factors ◽

Growth Factor ◽

Map Kinase ◽

Dominant Negative ◽

Neuroendocrine Cells ◽

Dependent Manner ◽

Epidermal Growth ◽

Dose Dependent

We have previously demonstrated that epidermal growth factor (EGF) produces activation of the rat prolactin (rPRL) promoter in GH4 neuroendocrine cells via a Ras-independent mechanism. This Ras independence of the EGF response appears to be cell rather than promoter specific. Oncogenic Ras also produces activation of the rPRL promoter when transfected into GH4 cells and requires the sequential activation of Raf kinase, mitogen-activated protein (MAP) kinase, and c-Ets-1/GHF-1 to mediate this response. In these studies, we have investigated the interaction between EGF and Ras in stimulating rPRL promoter activity and the role of Raf and MAP kinases in mediating the EGF response. We have also examined the role of several transcription factors and used various promoter mutants of the rPRL gene in order to better define the trans- and cis-acting components of the EGF response. EGF treatment of GH4 cells inhibits activation of the rPRL promoter produced by transfection of V12Ras from 24- to 4-fold in an EGF dose-dependent manner. This antagonistic effect of EGF and Ras is mutual in that transfection of V12Ras also blocks EGF-induced activation of the rPRL promoter in a Ras dose-dependent manner, from 5.5- to 1.6-fold. Transfection of a plasmid encoding the dominant-negative Raf C4 blocks Ras-induced activation by 66% but fails to inhibit EGF-mediated activation of the rPRL promoter. Similarly, transfection of a construct encoding an inhibitory form of MAP kinase decreases the Ras response by 50% but does not inhibit the EGF response. Previous studies have demonstrated that c-Ets-1 is necessary and that GHF-1 acts synergistically with c-Ets-1 in the Ras response of the rPRL promoter. In contrast, overexpression of neither c-Ets-1 nor GHF-1 enhanced EGF-mediated activation of the rPRL promoter, and dominant-negative forms of these transcription factors failed to inhibit the EGF response. Using 5' deletion and site-specific mutations, we have mapped the EGF response to two regions on the proximal rPRL promoter. One region maps between -255 and -212, near the Ras response element, and a second maps between -125 and -54. The latter region appears to involve footprint 2, a previously identified repressor site on the rPRL promoter. Neither footprint 1 nor 3, known GHF-1 binding sites, appears to be crucial to RGF-mediated rPRL promoter activation. The results of these studies indicate that in GH4 neuroendocrine cells, rPRL gene regulation by EGF is mediated by a signal transduction pathway that is separate and antagonistic to the Ras pathway. Hence, the functional role of the Ras/Raf/MAP kinase pathway in mediating transcriptional responses to EGF and other receptor tyrosine kinase may differ in highly specialized cell types.

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Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction

Journal of Cell Science ◽

10.1242/jcs.108.11.3599 ◽

1995 ◽

Vol 108 (11) ◽

pp. 3599-3609 ◽

Cited By ~ 4

Author(s):

E. Cano ◽

C.A. Hazzalin ◽

E. Kardalinou ◽

R.S. Buckle ◽

L.C. Mahadevan

Keyword(s):

Transcription Factors ◽

Map Kinase ◽

Uv Radiation ◽

Okadaic Acid ◽

Histone H3 ◽

Specificity Of Binding ◽

The Relationship ◽

Nuclear Response

The effects of EGF, TPA, UV radiation, okadaic acid and anisomycin on ERK and JNK/SAPK MAP kinase cascades have been compared with their ability to elicit histone H3/HMG-14 phosphorylation and induce c-fos and c-jun in C3H 10T1/2 cells. EGF and UV radiation activate both ERKs and JNK/SAPKs but to markedly different extents; EGF activates ERKs more strongly than JNK/SAPKs, whereas UV radiation activates JNK/SAPKs much more strongly than ERKs. Anisomycin and okadaic acid activate JNK/SAPKs but not ERKs, and conversely, TPA activates ERKs but not JNK/SAPKs. Nevertheless, all these agents elicit phosphorylation of ribosomal and pre-ribosomal S6, histone H3 and HMG-14, and the induction of c-fos and c-jun, showing that neither cascade is absolutely essential for these responses. We then analysed the relationship between ERKs, JNK/SAPKs and the transcription factors Elk-1 and c-Jun, implicated in controlling c-fos and c-jun, respectively. JNK/SAPKs bind to GST-cJun1-79, and ERKs, particularly ERK-2, to GST-Elk1(307–428); there is no cross-specificity of binding. Further, GST-Elk1(307–428) binds preferentially to active rather than inactive ERK-2. In vitro, JNK/SAPKs phosphorylate both GST-cJun1-79 and GST-Elk1(307–428), whereas ERKs phosphorylate GST-Elk1(307–428) but not GST-cJun1-79. Thus, neither ERKs nor JNK/SAPKs are absolutely essential for nuclear signalling and c-fos and c-jun induction. The data suggest either that activation of a single MAP kinase subtype is sufficient to elicit a complete nuclear response, or that other uncharacterised routes exist.

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