Insulin inhibits PDGF-directed VSMC migration via NO/ cGMP increase of MKP-1 and its inactivation of MAPKs

2002 ◽  
Vol 283 (3) ◽  
pp. C704-C713 ◽  
Author(s):  
Asha Jacob ◽  
Jeffery D. Molkentin ◽  
Albert Smolenski ◽  
Suzanne M. Lohmann ◽  
Najma Begum
Keyword(s):  
Protein Kinase ◽  
Inhibitory Effect ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Mapk Phosphorylation ◽  
Adenoviral Infection ◽  
Cgmp Signaling ◽  
Mitogen Activated Protein ◽  
And Migration ◽  
Insulin Inhibition

In this study, we examined the role of insulin in the control of vascular smooth muscle cell (VSMC) migration in the normal vasculature. Platelet-derived growth factor (PDGF) increased VSMC migration, which was inhibited by pretreatment with insulin in a dose-dependent manner. Insulin also caused a 60% decrease in PDGF-stimulated mitogen-activated protein kinase (MAPK) phosphorylation and activation. Insulin inhibition of MAPK was accompanied by a rapid induction of MAPK phosphatase (MKP-1), which inactivates MAPKs by dephosphorylation. Pretreatment with inhibitors of the nitric oxide (NO)/cGMP pathway, blocked insulin-induced MKP-1 expression and restored PDGF-stimulated MAPK activation and migration. In contrast, adenoviral infection of VSMCs with MKP-1 or cGMP-dependent protein kinase Iα (cGK Iα), the downstream effector of cGMP signaling, blocked the activation of MAPK and prevented PDGF-directed VSMC migration. Expression of antisense MKP-1 RNA prevented insulin's inhibitory effect and restored PDGF-directed VSMC migration and MAPK phosphorylation. We conclude that insulin inhibition of VSMC migration may be mediated in part by NO/cGMP/cGK Iα induction of MKP-1 and consequent inactivation of MAPKs.

scholarly journals Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B Lymphocytes

2008 ◽  
Vol 29 (3) ◽  
pp. 675-686 ◽  
Author(s):  
Jaclyn W. McAlees ◽  
Virginia M. Sanders
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Protein Tyrosine Phosphatase ◽  
Adrenergic Receptor ◽  
Tyrosine Phosphatase ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Mapk Activation ◽  
Mapk Phosphorylation ◽  
Mitogen Activated Protein

ABSTRACT Stimulation of the β2-adrenergic receptor (β2AR) on a CD40L/interleukin-4-activated B lymphocyte increases the level of immunoglobulin E (IgE) in a protein kinase A (PKA)- and p38 mitogen-activated protein kinase (MAPK)-dependent manner. However, the mechanism by which β2AR stimulation mediates the increase in the level of p38 MAPK activation has remained unclear. Here we show that the β2AR-induced increase in p38 MAPK activation occurred via a hematopoietic protein tyrosine phosphatase (HePTP)-mediated cross talk between PKA and p38 MAPK. β2AR agonists, cAMP-elevating agents, and PKA inhibitors were used to show that β2AR stimulation resulted in a PKA-dependent increase in p38 MAPK phosphorylation. Pharmacological agents and gene-deficient mice revealed that p38 MAPK phosphorylation was regulated by the G-stimulatory (Gs)/cAMP/PKA pathway independently of the G-inhibitory or β-arrestin-2 pathways. Coimmunoprecipitation and Western blot analysis showed that HePTP was phosphorylated in a PKA-dependent manner, which inactivated HePTP and allowed for increased free p38 MAPK to be phosphorylated by the MAPK cascade that was activated by CD40L. HePTP short hairpin RNA confirmed that HePTP played a role in regulating the level of p38 MAPK phosphorylation in a B cell. Thus, β2AR stimulation on a B cell phosphorylates and inactivates HePTP in a Gs/cAMP/PKA-dependent manner to release bound p38 MAPK, making more available for phosphorylation and subsequent IgE regulation.

scholarly journals Platyphyllenone Induces Autophagy and Apoptosis by Modulating the AKT and JNK Mitogen-Activated Protein Kinase Pathways in Oral Cancer Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 4211
Author(s):  
Yen-Tze Liu ◽  
Hsin-Yu Ho ◽  
Chia-Chieh Lin ◽  
Yi-Ching Chuang ◽  
Yu-Sheng Lo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Oral Cancer ◽  
Protein Expression ◽  
Caspase 3 ◽  
Therapeutic Option ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Cancer Proliferation ◽  
Mitogen Activated Protein

Platyphyllenone is a type of diarylheptanoid that exhibits anti-inflammatory and chemoprotective effects. However, its effect on oral cancer remains unclear. In this study, we investigated whether platyphyllenone can promote apoptosis and autophagy in SCC-9 and SCC-47 cells. We found that it dose-dependently promoted the cleavage of PARP; caspase-3, -8, and -9 protein expression; and also led to cell cycle arrest at the G2/M phase. Platyphyllenone up-regulated LC3-II and p62 protein expression in both SCC-9 and SCC-47 cell lines, implying that it can induce autophagy. Furthermore, the results demonstrated that platyphyllenone significantly decreased p-AKT and increased p-JNK1/2 mitogen-activated protein kinase (MAPK) signaling pathway in a dose-dependent manner. The specific inhibitors of p-JNK1/2 also reduced platyphyllenone-induced cleavage of PARP, caspase-3, and caspase -8, LC3-II and p62 protein expression. These findings are the first to demonstrate that platyphyllenone can induce both autophagy and apoptosis in oral cancers, and it is expected to provide a therapeutic option as a chemopreventive agent against oral cancer proliferation.

scholarly journals Phosphothreonine Lyase Promotes p65 Degradation in a Mitogen-Activated Protein Kinase/Mitogen- and Stress-Activated Protein Kinase 1-Dependent Manner

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Mingyu Hou ◽  
Wenhui Wang ◽  
Feizi Hu ◽  
Yuanxing Zhang ◽  
Dahai Yang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pathogenic Bacteria ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Content Type ◽  
Catalytic Active Site ◽  
Mitogen Activated Protein

ABSTRACT Bacterial phosphothreonine lyases have been identified to be type III secretion system (T3SS) effectors that irreversibly dephosphorylate host mitogen-activated protein kinase (MAPK) signaling to promote infection. However, the effects of phosphothreonine lyase on nuclear factor κB (NF-κB) signaling remain largely unknown. In this study, we detected significant phosphothreonine lyase-dependent p65 degradation during Edwardsiella piscicida infection in macrophages, and this degradative effect was blocked by the protease inhibitor MG132. Further analysis revealed that phosphothreonine lyase promotes the dephosphorylation and ubiquitination of p65 by inhibiting the phosphorylation of mitogen- and stress-activated protein kinase-1 (MSK1) and by inhibiting the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), p38α, and c-Jun N-terminal kinase (JNK). Moreover, we revealed that the catalytic active site of phosphothreonine lyase plays a critical role in regulating the MAPK-MSK1-p65 signaling axis. Collectively, the mechanism described here expands our understanding of the pathogenic effector in not only regulating MAPK signaling but also regulating p65. These findings uncover a new mechanism by which pathogenic bacteria overcome host innate immunity to promote pathogenesis.

scholarly journals The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1

Open Biology ◽  
2013 ◽  
Vol 3 (6) ◽  
pp. 130067 ◽  
Author(s):  
Gopal P. Sapkota
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Phosphorylation ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein

The signalling pathways downstream of the transforming growth factor beta (TGFβ) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi -mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

AMPK, MAPK and Bax in the heart: some questions answered

2008 ◽  
Vol 412 (2) ◽  
pp. e15-e16 ◽  
Author(s):  
Vilmante Borutaite
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Wide Field ◽  
Biochemical Journal ◽  
Mitogen Activated Protein ◽  
Isolated Cardiac Myocytes ◽  
And Migration ◽  
Induced Apoptosis ◽  
Amp Activated Protein Kinase ◽  
Rapid Activation

The question of how Bax is activated during apoptosis to perform its role in permeabilization of mitochondrial membranes is intriguing for investigators in the wide field of cell death research. In their paper published in the Biochemical Journal in 2006, Capano and Crompton presented their discovery that simulated ischaemia causes rapid activation of AMPK (AMP-activated protein kinase) which phosphorylates and activates p38 MAPK (mitogen-activated protein kinase) leading to Bax activation and translocation to mitochondria in isolated cardiac myocytes. This was the first report on the molecular mechanism of Bax activation and migration during ischaemia-induced apoptosis in cardiomyocytes.

scholarly journals A Redox-Sensitive Thiol in Wis1 Modulates the Fission Yeast Mitogen-Activated Protein Kinase Response to H2O2 and Is the Target of a Small Molecule

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Johanna J. Sjölander ◽  
Agata Tarczykowska ◽  
Cecilia Picazo ◽  
Itziar Cossio ◽  
Itedale Namro Redwan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fission Yeast ◽  
Inhibitory Effect ◽  
Mitogen Activated Protein Kinase ◽  
Activation Loop ◽  
Content Type ◽  
Kinase Activation ◽  
Mitogen Activated Protein

ABSTRACT Oxidation of a highly conserved cysteine (Cys) residue located in the kinase activation loop of mitogen-activated protein kinase kinases (MAPKK) inactivates mammalian MKK6. This residue is conserved in the fission yeast Schizosaccharomyces pombe MAPKK Wis1, which belongs to the H2O2-responsive MAPK Sty1 pathway. Here, we show that H2O2 reversibly inactivates Wis1 through this residue (C458) in vitro. We found that C458 is oxidized in vivo and that serine replacement of this residue significantly enhances Wis1 activation upon addition of H2O2. The allosteric MAPKK inhibitor INR119, which binds in a pocket next to the activation loop and C458, prevented the inhibition of Wis1 by H2O2 in vitro and significantly increased Wis1 activation by low levels of H2O2 in vivo. We propose that oxidation of C458 inhibits Wis1 and that INR119 cancels out this inhibitory effect by binding close to this residue. Kinase inhibition through the oxidation of a conserved Cys residue in MKK6 (C196) is thus conserved in the S. pombe MAPKK Wis1.

scholarly journals p44/42 mitogen-activated protein kinase is involved in the expression of ornithine decarboxylase in leukaemia L1210 cells

1999 ◽  
Vol 341 (2) ◽  
pp. 363-369 ◽  
Author(s):  
Flavio FLAMIGNI ◽  
Annalisa FACCHINI ◽  
Cristina CAPANNI ◽  
Claudio STEFANELLI ◽  
Benedetta TANTINI ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Ornithine Decarboxylase ◽  
Positive Impact ◽  
Mitogen Activated Protein Kinase ◽  
Lower Sensitivity ◽  
Mapk Phosphorylation ◽  
L1210 Cells ◽  
Signal Transduction Inhibitors ◽  
Mitogen Activated Protein

The involvement of p44/42 mitogen-activated protein kinase (MAPK) in the induction of ornithine decarboxylase (ODC) was investigated by using PD98059, a specific MAPK-kinase (MEK1/2) inhibitor, and other signal-transduction inhibitors. In D,L-α-difluoromethylornithine (DFMO)-resistant L1210 cells stimulated to grow from quiescence, treatment with PD98059 inhibited p44/42 MAPK phosphorylation and the induction of ODC activity and protein. A marked reduction of the accumulation of mature ODC mRNA and its intron-containing precursor was observed, whereas ODC turnover was hardly affected. PD98059 also reduced the content of antizyme, but not that of antizyme mRNA. U0126, a novel and more potent inhibitor of MEK1/2, provoked a dose-dependent inhibition of ODC induction at lower concentrations with respect to PD98059. Other effective inhibitors of ODC induction proved to be genistein, manumycin A, herbimycin A, LY294002, wortmannin and KT5823, suggesting the involvement of other key proteins of signal-transduction pathways, i.e. Ras, Src, phosphatidylinositol 3-kinase and cGMP-dependent protein kinase, which may have a positive impact on MAPK. Cells kept in a DFMO-free medium, and thus containing high levels of putrescine and spermidine, showed enhanced MAPK phosphorylation and lower sensitivity to PD98059, compared with cells maintained in the presence of DFMO. In conclusion, these results indicate that the activation of p44/42 MAPK may favour the expression of ODC, and that polyamines, in turn, may affect the phosphorylation state of MAPK.

scholarly journals The Mitogen-activated Protein Kinase p38 Links Shiga Toxin-dependent Signaling and Trafficking

2008 ◽  
Vol 19 (1) ◽  
pp. 95-104 ◽  
Author(s):  
Sébastien Wälchli ◽  
Sigrid S. Skånland ◽  
Tone F. Gregers ◽  
Silje U. Lauvrak ◽  
Maria L. Torgersen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Golgi Apparatus ◽  
Shiga Toxin ◽  
Intracellular Transport ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Early Endosomes ◽  
Chemical Inhibitors ◽  
Mitogen Activated Protein ◽  
Interfering Rna

Shiga toxin (Stx) binds to the cell, and it is transported via endosomes and the Golgi apparatus to the endoplasmic reticulum and cytosol, where it exerts its toxic effect. We have recently shown that Stx activates the tyrosine kinase Syk, which in turn induces clathrin phosphorylation and up-regulates Stx uptake. Here, we show that toxin-induced signaling can also regulate another step in intracellular Stx transport. We demonstrate that transport of Stx to the Golgi apparatus is dependent on the mitogen-activated protein kinase p38. Treatment of cells with chemical inhibitors or small interfering RNA targeting p38 inhibited Stx transport to the Golgi and reduced Stx toxicity. This p38 dependence is specific to Stx, because transport of the related toxin ricin was not affected by p38 inhibition. Stx rapidly activated p38, and recruited it to early endosomes in a Ca2+-dependent manner. Furthermore, agonist-induced oscillations in cytosolic Ca2+levels were inhibited upon Stx stimulation, possibly reflecting Stx-dependent local alterations in cytosolic Ca2+levels. Intracellular transport of Stx is Ca2+dependent, and we provide evidence that Stx activates a signaling cascade involving cross talk between Ca2+and p38, to regulate its trafficking to the Golgi apparatus.

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