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

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.

Download Full-text

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.

Download Full-text

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

Journal of Cellular Physiology ◽

10.1002/jcp.25102 ◽

2015 ◽

Vol 231 (3) ◽

pp. 587-596 ◽

Cited By ~ 63

Author(s):

Chunxi Ge ◽

William P. Cawthorn ◽

Yan Li ◽

Guisheng Zhao ◽

Ormond A. MacDougald ◽

...

Keyword(s):

Transcription Factors ◽

Map Kinase ◽

Adipogenic Differentiation ◽

Kinase Phosphorylation

Download Full-text

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.

Download Full-text