Novel regulation of adrenomedullin receptor by PDGF: role of receptor activity modifying protein-3

2002 ◽  
Vol 282 (6) ◽  
pp. C1322-C1331 ◽  
Author(s):  
Wojciech Nowak ◽  
Narayanan Parameswaran ◽  
Carolyn S. Hall ◽  
Nambi Aiyar ◽  
Harvey V. Sparks ◽  
...  
Keyword(s):  
Mesangial Cells ◽  
Receptor Activity ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Calcitonin Receptor ◽  
Concentration Dependent Manner ◽  
Adrenomedullin Receptor ◽  
Mitogen Activated Protein ◽  
Functional Receptor

Receptor activity modifying protein-3 (RAMP-3) has been shown to complex with the calcitonin receptor-like receptor, establishing a functional receptor for adrenomedullin (AM). AM exhibits potent antiproliferative and antimigratory effects on rat mesangial cells (RMCs). In this study we investigated the effect of platelet-derived growth factor (PDGF) on RAMP-3 expression in RMCs. We show here that PDGF-BB stimulates RAMP-3 mRNA expression in a concentration-dependent manner. Pretreatment with actinomycin-D and α-amanitin demonstrates that this effect is independent of new RNA synthesis. Furthermore, PDGF increased the half-life of RAMP-3 mRNA from 66.5 to 331.6 min. Using selective inhibitors, our results also indicate that the increase in RAMP-3 mRNA is mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK and p38 MAPK dependent. PDGF also caused a corresponding elevation in membrane-associated RAMP-3 protein. Associated with this increase, PDGF pretreatment led to a significantly higher AM-mediated adenylate cyclase activity, suggesting a functional consequence for the PDGF-induced increase in RAMP-3 expression. Taken together, these data identify PDGF-dependent regulation of RAMP-3 expression as a possible mechanism for modulating the responsiveness of the mesangial cell to AM.

α1-Adrenergic and cholinergic agonists activate MAPK by separate mechanisms to inhibit secretion in lacrimal gland

2003 ◽  
Vol 284 (1) ◽  
pp. C168-C178 ◽  
Author(s):  
Isao Ota ◽  
Driss Zoukhri ◽  
Robin R. Hodges ◽  
José D. Rios ◽  
Vanja Tepavcevic ◽  
...  
Keyword(s):  
Protein Secretion ◽  
Lacrimal Gland ◽  
Egf Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Signaling Mechanisms ◽  
Mitogen Activated Protein ◽  
Secretion Inhibition

The purpose of this study was to determine the role of p42/p44 mitogen-activated protein kinase (MAPK) in α1-adrenergically and cholinergically stimulated protein secretion in rat lacrimal gland acinar cells and the pathways used by these agonists to activate MAPK. Acini were isolated by collagenase digestion and incubated with the α1-adrenergic agonist phenylephrine or the cholinergic agonist carbachol, and activation of MAPK and protein secretion were then measured. Phenylephrine and carbachol activated MAPK in a time- and concentration-dependent manner. Inhibition of MAPK significantly increased phenylephrine- and carbachol-induced protein secretion. Inhibition of EGF receptor (EGFR) with AG1478, an inhibitor of the EGFR tyrosine kinase activity, significantly increased phenylephrine- but not carbachol-induced protein secretion. Whereas phenylephrine-induced activation of MAPK was completely inhibited by AG1478, activation of MAPK by carbachol was not. Phenylephrine stimulated tyrosine phosphorylation of the EGFR, whereas carbachol stimulated p60Src, and possibly Pyk2, to activate MAPK. We conclude that, in the lacrimal gland, activation of MAPK plays an inhibitory role in α1-adrenergically and cholinergically stimulated protein secretion and that these agonists use different signaling mechanisms to activate MAPK.

Poria cocosInhibits High Glucose-Induced Proliferation of Rat Mesangial Cells

2013 ◽  
Vol 41 (01) ◽  
pp. 71-83 ◽  
Author(s):  
Jung Joo Yoon ◽  
Yun Jung Lee ◽  
So Min Lee ◽  
Song Nan Jin ◽  
Dae Gill Kang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
High Glucose ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Water Extract ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Proliferative Effect ◽  
Mesangial Cell Proliferation ◽  
Mitogen Activated Protein

Mesangial cell proliferation is correlated with the progression of renal failure. The purpose of this study was to determine whether a water extract of Poria cocos Wolf (WPC), a well-known medicinal plant, regulates rat mesangial cell proliferation in the presence of high glucose (HG). HG significantly accelerated [3H]-thymidine incorporation, which was inhibited by WPC (1–50 μg/mL) in a dose-dependent manner. Cell migration and fibronectin mRNA expression data also supported the anti-proliferative effect of WPC. Western blot analysis revealed that pretreatment with WPC decreased the expression of cyclins and cyclin-dependent kinases (CDKs) and promoted the expression of p21waf1/cip1and p27kip1. WPC also suppressed HG-induced p38 mitogen-activated protein kinase (p38 MAPK) and extracellular-signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Furthermore, WPC inhibited HG-induced production of dichlorofluorescein (DCF)-sensitive intracellular reactive oxygen species (ROS). In conclusion, HG promoted mesangial cell proliferation, and WPC inhibited this activity, at least in part, via induction of cell cycle arrest and activation of anti-oxidant properties. Taken together, these results suggest that P. cocos may be a potent regulator of HG-induced proliferation.

scholarly journals EphA2 is a functional receptor for the growth factor progranulin

2016 ◽  
Vol 215 (5) ◽  
pp. 687-703 ◽  
Author(s):  
Thomas Neill ◽  
Simone Buraschi ◽  
Atul Goyal ◽  
Catherine Sharpe ◽  
Elizabeth Natkanski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Solid Phase ◽  
Large Family ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Mitogen Activated Protein ◽  
Functional Receptor ◽  
Autoregulatory Mechanism

Although the growth factor progranulin was discovered more than two decades ago, the functional receptor remains elusive. Here, we discovered that EphA2, a member of the large family of Ephrin receptor tyrosine kinases, is a functional signaling receptor for progranulin. Recombinant progranulin bound with high affinity to EphA2 in both solid phase and solution. Interaction of progranulin with EphA2 caused prolonged activation of the receptor, downstream stimulation of mitogen-activated protein kinase and Akt, and promotion of capillary morphogenesis. Furthermore, we found an autoregulatory mechanism of progranulin whereby a feed-forward loop occurred in an EphA2-dependent manner that was independent of the endocytic receptor sortilin. The discovery of a functional signaling receptor for progranulin offers a new avenue for understanding the underlying mode of action of progranulin in cancer progression, tumor angiogenesis, and perhaps neurodegenerative diseases.

LPA is a novel lipid regulator of mesangial cell hexokinase activity and HKII isoform expression

2002 ◽  
Vol 283 (2) ◽  
pp. F271-F279 ◽  
Author(s):  
Platina E. Coy ◽  
Navin Taneja ◽  
Iris Lee ◽  
Claudie Hecquet ◽  
Jane M. Bryson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Glomerular Injury ◽  
Mitogen Activated Protein ◽  
Extracellular Lipid ◽  
Cell Mitogen

The prototypical extracellular phospholipid mediator, lysophosphatidic acid (LPA), exhibits growth factor-like properties and represents an important survival factor in serum. This potent mesangial cell mitogen is increased in conditions associated with glomerular injury. It is also a known activator of the classic mitogen-activated protein kinase (MAPK) pathway, which plays an important role in the regulation of mesangial cell hexokinase (HK) activity. To better understand the mechanisms coupling metabolism to injury, we examined the ability of LPA to regulate HK activity and expression in cultured murine mesangial cells. LPA increased total HK activity in a concentration- and time-dependent manner, with maximal increases of >50% observed within 12 h of exposure to LPA concentrations ≥25 μM (apparent ED50 2 μM). These effects were associated with increased extracellular signal-regulated kinase (ERK) activity and were prevented by the pharmacological inhibition of either MAPK/ERK kinase or protein kinase C (PKC). Increased HK activity was also associated with increased glucose (Glc) utilization and lactate accumulation, as well as selectively increased HKII isoform abundance. The ability of exogenous LPA to increase HK activity was both Ca2+independent and pertussis toxin insensitive and was mimicked by LPA-generating phospholipase A2. We conclude that LPA constitutes a novel lipid regulator of mesangial cell HK activity and Glc metabolism. This regulation requires sequential activation of both Ca2+-independent PKC and the classic MAPK pathway and culminates in increased HKII abundance. These previously unrecognized metabolic consequences of LPA stimulation have both physiological and pathophysiological implications. They also suggest a novel mechanism whereby metabolism may be coupled to cellular injury via extracellular lipid mediators.

scholarly journals Anti-Photoaging and Anti-Melanogenesis Effects of Fucoidan Isolated from Hizikia fusiforme and Its Underlying Mechanisms

Marine Drugs ◽  
2020 ◽  
Vol 18 (8) ◽  
pp. 427 ◽  
Author(s):  
Lei Wang ◽  
Jae-Young Oh ◽  
Young-Sang Kim ◽  
Hyo-Geun Lee ◽  
Jung-Suck Lee ◽  
...  
Keyword(s):  
Human Keratinocytes ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Hacat Cells ◽  
Concentration Dependent Manner ◽  
B16f10 Cells ◽  
Hizikia Fusiforme ◽  
Mitogen Activated Protein ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Previous studies suggested that fucoidan with a molecular weight of 102.67 kDa, isolated from Hizikia fusiforme, possesses strong antioxidant activity. To explore the cosmeceutical potential of fucoidan, its anti-photoaging and anti-melanogenesis effects were evaluated in the present study. The anti-photoaging effect was investigated in ultraviolet (UV) B-irradiated human keratinocytes (HaCaT cells), where fucoidan effectively reduced the intracellular reactive oxygen species level and improved the viability of the UVB-irradiated cells without any cytotoxic effects. Moreover, fucoidan significantly decreased UVB-induced apoptosis in HaCaT cells by regulating the protein expression of Bax, Bcl-xL, PARP, and Caspase-3 in HaCaT cells in a concentration-dependent manner. The anti-melanogenesis effect of fucoidan was evaluated in B16F10 melanoma cells that had been stimulated with alpha-melanocyte-stimulating hormone (α-MSH), and fucoidan treatment remarkably inhibited melanin synthesis in α-MSH-stimulated B16F10 cells. Further studies indicated that fucoidan significantly suppressed the expression of tyrosinase and tyrosinase-related protein-1 and -2 (TRP-1 and-2) in B16F10 cells by down-regulating microphthalmia-associated transcription factor (MITF) through regulation of the ERK–MAPK (extracellular signal regulated kinase-mitogen activated protein kinase) pathway. Taken together, these results suggest that fucoidan isolated from H. fusiforme possesses strong anti-photoaging and anti-melanogenesis activities and can be used as an ingredient in the pharmaceutical and cosmeceutical industries.

Sphingosine Blocks Human Polymorphonuclear Leukocyte Phagocytosis Through Inhibition of Mitogen-Activated Protein Kinase Activation

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 686-693 ◽  
Author(s):  
Evelin M.B. Raeder ◽  
Pamela J. Mansfield ◽  
Vania Hinkovska-Galcheva ◽  
Lars Kjeldsen ◽  
James A. Shayman ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Protein Kinase ◽  
Polymorphonuclear Leukocyte ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Human Polymorphonuclear Leukocyte ◽  
Calcium Dependent ◽  
Mitogen Activated Protein ◽  
Erk2 Activation

Abstract In the present study, we investigated the mechanism by which sphingosine and its analogues, dihydrosphingosine and phytosphingosine, inhibit polymorphonuclear leukocyte (PMN) phagocytosis of IgG-opsonized erythrocytes (EIgG) and inhibit ERK1 and ERK2 phosphorylation. We used antibodies that recognized the phosphorylated forms of ERK1 (p44) and ERK2 (p42) (extracellular signal-regulated protein kinases 1 and 2). Sphingoid bases inhibited ERK1 and ERK2 activation and phagocytosis of EIgG in a concentration-dependent manner. Incubation with glycine, N,N′-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]]-bis[(acetyloxy)methyl]ester (BAPTA,AM), an intracellular chelator of calcium, failed to block either phagocytosis or ERK1 and ERK2 phosphorylation, consistent with the absence of a role for a calcium-dependent protein kinase C (PKC) in ERK1 and ERK2 phosphorylations. Western blotting demonstrated that sphingosine inhibited the translocation of Raf-1 and PKCδ from PMN cytosol to the plasma membrane during phagocytosis. These data are consistent with the interpretation that sphingosine regulates ERK1 and ERK2 phosphorylation through inhibition of PKCδ, and this in turn leads to inhibition of Raf-1 translocation to the plasma membrane. Consistent with this interpretation, the sphingosine-mediated inhibition of phagocytosis, ERK2 activation, and PKCδ translocation to the plasma membrane could be abrogated with a cell-permeable diacylglycerol analog. The increase in the diacylglycerol mass correlated with the translocation of PKCδ and Raf-1 to the plasma membrane by 3 minutes after the initiation of phagocytosis. Additionally, the diacylglycerol analog enhanced phagocytosis by initiating activation of PKCδ and its translocation to the plasma membrane. Because PMN generate sufficient levels of sphingosine by 30 minutes during phagocytosis of EIgG to inhibit phagocytosis, it appears that sphingosine can serve as an endogenous regulator of EIgG-mediated phagocytosis by downregulating ERK activation.

Sphingosine Blocks Human Polymorphonuclear Leukocyte Phagocytosis Through Inhibition of Mitogen-Activated Protein Kinase Activation

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 686-693 ◽  
Author(s):  
Evelin M.B. Raeder ◽  
Pamela J. Mansfield ◽  
Vania Hinkovska-Galcheva ◽  
Lars Kjeldsen ◽  
James A. Shayman ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Protein Kinase ◽  
Polymorphonuclear Leukocyte ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Human Polymorphonuclear Leukocyte ◽  
Calcium Dependent ◽  
Mitogen Activated Protein ◽  
Erk2 Activation

In the present study, we investigated the mechanism by which sphingosine and its analogues, dihydrosphingosine and phytosphingosine, inhibit polymorphonuclear leukocyte (PMN) phagocytosis of IgG-opsonized erythrocytes (EIgG) and inhibit ERK1 and ERK2 phosphorylation. We used antibodies that recognized the phosphorylated forms of ERK1 (p44) and ERK2 (p42) (extracellular signal-regulated protein kinases 1 and 2). Sphingoid bases inhibited ERK1 and ERK2 activation and phagocytosis of EIgG in a concentration-dependent manner. Incubation with glycine, N,N′-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]]-bis[(acetyloxy)methyl]ester (BAPTA,AM), an intracellular chelator of calcium, failed to block either phagocytosis or ERK1 and ERK2 phosphorylation, consistent with the absence of a role for a calcium-dependent protein kinase C (PKC) in ERK1 and ERK2 phosphorylations. Western blotting demonstrated that sphingosine inhibited the translocation of Raf-1 and PKCδ from PMN cytosol to the plasma membrane during phagocytosis. These data are consistent with the interpretation that sphingosine regulates ERK1 and ERK2 phosphorylation through inhibition of PKCδ, and this in turn leads to inhibition of Raf-1 translocation to the plasma membrane. Consistent with this interpretation, the sphingosine-mediated inhibition of phagocytosis, ERK2 activation, and PKCδ translocation to the plasma membrane could be abrogated with a cell-permeable diacylglycerol analog. The increase in the diacylglycerol mass correlated with the translocation of PKCδ and Raf-1 to the plasma membrane by 3 minutes after the initiation of phagocytosis. Additionally, the diacylglycerol analog enhanced phagocytosis by initiating activation of PKCδ and its translocation to the plasma membrane. Because PMN generate sufficient levels of sphingosine by 30 minutes during phagocytosis of EIgG to inhibit phagocytosis, it appears that sphingosine can serve as an endogenous regulator of EIgG-mediated phagocytosis by downregulating ERK activation.

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.

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