Role of pp60c-src andp44/42 MAPK in ANG II-induced contraction of rat tonic gastrointestinal smooth muscles

2002 ◽  
Vol 283 (2) ◽  
pp. G390-G399 ◽  
Author(s):  
Rajinder N. Puri ◽  
Ya-Ping Fan ◽  
Satish Rattan
Keyword(s):  
Smooth Muscles ◽  
Specific Inhibitor ◽  
Effector Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Ang Ii ◽  
Herbimycin A ◽  
Before And After ◽  
Mitogen Activated Protein ◽  
Induced Changes

We examined the role of mitogen-activated protein kinase ( p44/42 MAPK) in ANG II-induced contraction of lower esophageal sphincter (LES) and internal anal sphincter (IAS) smooth muscles. Studies were performed in the isolated smooth muscles and cells (SMC). ANG II-induced changes in the levels of phosphorylation of different signal transduction and effector proteins were determined before and after selective inhibitors. ANG II-induced contraction of the rat LES and IAS SMC was inhibited by genistein, PD-98059 [a specific inhibitor of MAPK kinases (MEK 1/2)], herbimycin A (a pp60c-src inhibitor), and antibodies to pp60c-src and p120ras GTPase-activating protein ( p120rasGAP). ANG II-induced contraction of the tonic smooth muscles was accompanied by an increase in tyrosine phosphorylation of p120 rasGAP. These were attenuated by genistein but not by PD-98059. ANG II-induced increase in phosphorylations of p44/42 MAPKs and caldesmon was attenuated by both genistein and PD-98059. We conclude that pp60c-src and p44/42 MAPKs play an important role in ANG II-induced contraction of LES and IAS smooth muscles.

AT1 receptors in the nucleus tractus solitarii mediate the interaction between the baroreflex and the cardiac sympathetic afferent reflex in anesthetized rats

2007 ◽  
Vol 292 (3) ◽  
pp. R1137-R1145 ◽  
Author(s):  
Wei-Zhong Wang ◽  
Lie Gao ◽  
Yan-Xia Pan ◽  
Irving H. Zucker ◽  
Wei Wang
Keyword(s):  
Extracellular Recording ◽  
Nucleus Tractus Solitarii ◽  
Ang Ii ◽  
Baroreflex Control ◽  
Anesthetized Rats ◽  
Before And After ◽  
Cardiac Sympathetic Afferent Reflex ◽  
Induced Changes

The cardiac “sympathetic afferent” reflex (CSAR) has been reported to increase sympathetic outflow and depress baroreflex function via a central angiotensin II (ANG II) mechanism. In the present study, we examined the role of ANG II type 1 (AT1) receptors in the nucleus tractus solitarii (NTS) in mediating the interaction between the CSAR and the baroreflex in anesthetized rats. We examined the effects of bilateral microinjection of AT1 receptor antagonist losartan (100 pmol) into the NTS on baroreflex control of renal sympathetic nerve activity (RSNA) before and after CSAR activation by epicardial application of capsaicin (0.4 μg). Using single-unit extracellular recording, we further examined the effects of CSAR activation on the barosensitivity of barosensitive NTS neurons and the effects of intravenous losartan (2 mg/kg) on CSAR-induced changes in activity of NTS barosensitive neurons. Bilateral NTS microinjection of losartan significantly attenuated the increases in arterial pressure, heart rate, and RSNA evoked by capsaicin but also markedly ( P < 0.01) reversed the CSAR-induced blunted baroreflex control of RSNA (Gainmax from 1.65 ± 0.10 to 2.22 ± 0.11%/mmHg). In 17 of 24 (70.8%) NTS barosensitive neurons, CSAR activation significantly ( P < 0.01) inhibited the baseline neuronal activity and attenuated the neuronal barosensitivity. In 11 NTS barosensitive neurons, intravenous losartan effectively ( P < 0.01) normalized the decreased neuronal barosensitivity induced by CSAR activation. In conclusion, blockade of NTS AT1 receptors improved the blunted baroreflex during CSAR activation, suggesting that the NTS plays an important role in processing the interaction between the baroreflex and the CSAR via an AT1 receptor-dependent mechanism.

scholarly journals CD40 Signaling Is Impaired in L. major–infected Macrophages and Is Rescued by a p38MAPK Activator Establishing a Host-protective Memory T Cell Response

2003 ◽  
Vol 197 (8) ◽  
pp. 1037-1043 ◽  
Author(s):  
Amit Awasthi ◽  
Ramkumar Mathur ◽  
Aslam Khan ◽  
Bimba N. Joshi ◽  
Nitya Jain ◽  
...  
Keyword(s):  
Drug Targets ◽  
Specific Inhibitor ◽  
Protozoan Parasite ◽  
Parasite Load ◽  
Cd40 Ligand ◽  
T Cell Response ◽  
Mitogen Activated Protein Kinase ◽  
Leishmania Infection ◽  
Mitogen Activated Protein

Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-γ, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major–infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK)-specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD40-induced p38MAPK phosphorylation, iNOS2 expression and anti-leishmanial function were impaired in Leishmania-infected macrophages but were restored by anisomycin. Anisomycin's effects were reversed by SB203580 emphasizing the role of p38MAPK in CD40-induced iNOS2-dependent leishmanicidal function. Anisomycin administration in L. major–infected BALB/c mice resulted in significant reduction in the parasite load and established a host-protective Th1-type memory response. Also implicated in these findings is a scientific rationale to define novel anti-parasite drug targets and to bypass the problem of drug resistance.

scholarly journals I-κB Kinase-ε Deficiency Attenuates the Development of Angiotensin II-Induced Myocardial Hypertrophy in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yide Cao ◽  
Liangpeng Li ◽  
Yafeng Liu ◽  
Ganyi Chen ◽  
Zhonghao Tao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Myocardial Hypertrophy ◽  
Peptide Hormone ◽  
Mitogen Activated Protein Kinase ◽  
Mouse Heart ◽  
Ang Ii ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

I-κB kinase-ε (IKKε) is a member of the IKK complex and a proinflammatory regulator that is active in many diseases. Angiotensin II (Ang II) is a vasoconstricting peptide hormone, and Ang II-induced myocardial hypertrophy is a common cardiovascular disease that can result in heart failure. In this study, we sought to determine the role of IKKε in the development of Ang II-induced myocardial hypertrophy in mice. Wild-type (WT) and IKKε-knockout (IKKε-KO) mice were generated and infused with saline or Ang II for 8 weeks. We found that WT mouse hearts have increased IKKε expression after 8 weeks of Ang II infusion. Our results further indicated that IKKε-KO mice have attenuated myocardial hypertrophy and alleviated heart failure compared with WT mice. Additionally, Ang II-induced expression of proinflammatory and collagen factors was much lower in the IKKε-KO mice than in the WT mice. Apoptosis and pyroptosis were also ameliorated in IKKε-KO mice. Mechanistically, IKKε bound to extracellular signal-regulated kinase (ERK) and the mitogen-activated protein kinase p38, resulting in MAPK/ERK kinase (MEK) phosphorylation, and IKKε deficiency inhibited the phosphorylation of MEK-ERK1/2 and p38 in mouse heart tissues after 8 weeks of Ang II infusion. The findings of our study reveal that IKKε plays an important role in the development of Ang II-induced myocardial hypertrophy and may represent a potential therapeutic target for the management of myocardial hypertrophy.

scholarly journals Mitotic Phosphorylation of Golgi Reassembly Stacking Protein 55 by Mitogen-activated Protein Kinase ERK2

2001 ◽  
Vol 12 (6) ◽  
pp. 1811-1817 ◽  
Author(s):  
Stephen A. Jesch ◽  
Timothy S. Lewis ◽  
Natalie G. Ahn ◽  
Adam D. Linstedt
Keyword(s):  
Protein Kinase ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Erk Activation ◽  
Mitogen Activated Protein ◽  
Mitotic Phosphorylation

The role of the mitogen-activated protein kinase kinase (MKK)/extracellular-activated protein kinase (ERK) pathway in mitotic Golgi disassembly is controversial, in part because Golgi-localized targets have not been identified. We observed that Golgi reassembly stacking protein 55 (GRASP55) was phosphorylated in mitotic cells and extracts, generating a mitosis-specific phospho-epitope recognized by the MPM2 mAb. This phosphorylation was prevented by mutation of ERK consensus sites in GRASP55. GRASP55 mitotic phosphorylation was significantly reduced, both in vitro and in vivo, by treatment with U0126, a potent and specific inhibitor of MKK and thus ERK activation. Furthermore, ERK2 directly phosphorylated GRASP55 on the same residues that generated the MPM2 phospho-epitope. These results are the first demonstration of GRASP55 mitotic phosphorylation and indicate that the MKK/ERK pathway directly phosphorylates the Golgi during mitosis.

scholarly journals Regulation of ERK2 activity by dynamic S-acylation

2021 ◽  
Author(s):  
Saara-Anne Azizi ◽  
Tian Qiu ◽  
Noah Brookes ◽  
Bryan C Dickinson
Keyword(s):  
Mapk Pathway ◽  
Effector Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Post Translational Modifications ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Key Sites ◽  
Egf Signaling

The extracellular signal-regulated kinases (ERK1/2) are key effector proteins of the mitogen activated protein kinase pathway, choreographing essential processes of cellular physiology. Critical in regulating these regulators are a patchwork of mechanisms, including post-translational modifications (PTMs) such as MEK-mediated phosphorylation. Here, we discover that ERK1/2 are subject to S-palmitoylation, a reversible lipid modification of cysteine residues, at C271/C254. Moreover, the levels of ERK1/2 S-acylation are modulated by epidermal growth factor (EGF) signaling, mirroring its phosphorylation dynamics, and palmitoylation-deficient ERK2 displays altered phosphorylation patterns at key sites. We find that chemical inhibition of either lipid addition or removal significantly alters ERK1/2's EGF-triggered transcriptional program. We also identify a subset of "writer" protein acyl transferases (PATs) and an "eraser" acyl protein thioesterase (APT) that drive ERK1/2's cycle of palmitoylation and depalmitoylation. Finally, we examine ERK1/2 S-acylation in a mouse model of metabolic syndrome, correlating changes in its lipidation levels with alterations in writer/eraser expression and solidifying the link between ERK1/2 activity, ERK1/2 lipidation, and organismal health. This study not only presents a previously undescribed mode of ERK1/2 regulation and a node to modulate MAPK pathway signaling in pathophysiological conditions, it also offers insight into the role of dynamic S29 palmitoylation in cell signaling more generally.

scholarly journals Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes

2006 ◽  
Vol 36 (2) ◽  
pp. 377-388 ◽  
Author(s):  
Young Sun Kang ◽  
Yun Gyu Park ◽  
Bo Kyung Kim ◽  
Sang Youb Han ◽  
Yi Hwa Jee ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Ang Ii ◽  
Vegf Mrna ◽  
Mitogen Activated Protein ◽  
Endothelial Growth Factor

Angiotensin II (Ang-II) and vascular endothelial growth factor (VEGF) have an important role in the pathogenesis of diabetic nephropathy, but the signaling cascade of VEGF regulation in response to Ang-II in podocytes is largely unknown. In these experiments, we looked at the effect of Ang-II on the production of VEGF, and investigated whether VEGF production depends on the p38 mitogen activated protein kinase (MAPK) pathway in cultured mouse podocytes. Incubation of podocytes with Ang-II induced a rapid increase in VEGF mRNA expression and protein synthesis as well as its transcriptional activity in an Ang-II dose-dependent manner. To further define the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors involved in Ang-II-mediated VEGF synthesis, the effects of selective AT1 and AT2 receptor antagonists were evaluated. Prior treatment with losartan significantly inhibited VEGF mRNA and protein synthesis induced by Ang-II, which suggests that the AT1 receptor is involved in Ang-II-mediated VEGF synthesis. Furthermore, stimulation of the cells with Ang-II increased both phosphorylation of p38 MAPK and MAP kinase kinase 3/6 (MKK3/6). Additionally, Ang-II enhanced the DNA binding activity to cAMP response element binding protein (CREB) and phosphorylation of CREB. In addition, to investigate the role of p38 MAPK in Ang-II-induced VEGF synthesis, podocytes were pretreated with or without the p38 MAPK inhibitor, SB203580 for 24 h to observe whether Ang-II-mediated VEGF synthesis was inhibited by blocking p38 MAPK. The addition of SB203580 led to a marked inhibition of the increased VEGF mRNA and protein production induced by Ang-II in a dose-dependent manner. Taken together, these results suggest that Ang-II stimulates the synthesis of VEGF in podocytes and the production of VEGF induced by Ang-II is mediated, in part, through the activation of the p38 MAPK pathway.

scholarly journals Differential Role of Threonine and Tyrosine Phosphorylation in the Activation and Activity of the Yeast MAPK Slt2

2021 ◽  
Vol 22 (3) ◽  
pp. 1110
Author(s):  
Gema González-Rubio ◽  
Ángela Sellers-Moya ◽  
Humberto Martín ◽  
María Molina
Keyword(s):  
Cell Wall ◽  
Biological Activity ◽  
Biological Significance ◽  
Mitogen Activated Protein Kinase ◽  
Activation Loop ◽  
High Increase ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Full Activation

The Mitogen-Activated Protein Kinase (MAPK) Slt2 is central to signaling through the yeast Cell Wall Integrity (CWI) pathway. MAPKs are regulated by phosphorylation at both the threonine and tyrosine of the conserved TXY motif within the activation loop (T190/Y192 in Slt2). Since phosphorylation at both sites results in the full activation of MAPKs, signaling through MAPK pathways is monitored with antibodies that detect dually phosphorylated forms. However, most of these antibodies also recognize monophosphorylated species, whose relative abundance and functionality are diverse. By using different phosphospecific antibodies and phosphate-affinity (Phos-tag) analysis on distinct Slt2 mutants, we determined that Y192- and T190-monophosphorylated species coexist with biphosphorylated Slt2, although most of the Slt2 pool remains unphosphorylated following stress. Among the monophosphorylated forms, only T190 exhibited biological activity. Upon stimulation, Slt2 is first phosphorylated at Y192, mainly by the MAPKK Mkk1, and this phosphorylation is important for the subsequent T190 phosphorylation. Similarly, dephosphorylation of Slt2 by the Dual Specificity Phosphatase (DSP) Msg5 is ordered, with dephosphorylation of T190 depending on previous Y192 dephosphorylation. Whereas Y192 phosphorylation enhances the Slt2 catalytic activity, T190 is essential for this activity. The conserved T195 residue is also critical for Slt2 functionality. Mutations that abolish the activity of Slt2 result in a high increase in inactive Y192-monophosphorylated Slt2. The coexistence of different Slt2 phosphoforms with diverse biological significance highlights the importance of the precise detection of the Slt2 phosphorylation status.

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