Kinetic and mechanistic studies of p38α
            MAP
            kinase phosphorylation by
            MKK
            6

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>

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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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