scholarly journals Differential regulation of the dual-specificity protein-tyrosine phosphatases CL100, B23, and PAC1 in mesangial cells.

1997 ◽  
Vol 8 (1) ◽  
pp. 40-50
Author(s):  
D Bokemeyer ◽  
A Sorokin ◽  
M J Dunn
Keyword(s):  
Map Kinase ◽  
Intracellular Signaling ◽  
Map Kinases ◽  
Mesangial Cells ◽  
Feedback Inhibition ◽  
Protein Tyrosine Phosphatases ◽  
P38 Map Kinase ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Dual Specificity

The extracellular-signal-regulated kinase (ERK), the best described MAP kinase cascade, is a major signaling system by which cells transduce extracellular cues into intracellular responses. ERK is activated by phosphorylation both on tyrosine and threonine residues. Therefore, a new clas of protein-tyrosine phosphatases (PTPases) that exhibit dual catalytic activity toward both regulatory sites on ERK is of special interest in the control of intracellular signaling. This study examined the expression and regulation of the dual-specificity PTPases CL100, B23, and PAC1. Findings included differential expression of these phosphatases in diverse cell lines and an expression of all three dual-specificity PTPases in human mesangial cells (HMC), thereby allowing investigation of their regulation in a single cell line. The MEK antagonist PD 098059 and selective extracellular agonists of ERK were used to demonstrate the induction of CL100, PAC1, and B23 in response to activation of the ERK cascade. In contrast, anisomycin, an agonist of the recently described MAP kinases stress-activated protein kinase (SAPK) and p38 MAP kinase, stimulated CL100 gene expression but had little effect on PAC1 and B23. This effect of anisomycin was partly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. This study suggests a potential mechanism to regulate ERK activity through feedback inhibition by demonstrating the ERK cascade's induction of the dual-specificity PTPases CL100, PAC1, and B23. Moreover, this study suggests an ERK-independent induction of CL100 following stimulation of SAPK and p38 MAP kinase. This mode of induction of a phosphatase capable of inactivating ERK may play an important role in the cellular stress response.

Spontaneous activation of the NF-κB signaling pathway in isolated normal glomeruli

2006 ◽  
Vol 291 (6) ◽  
pp. F1169-F1176 ◽  
Author(s):  
Kunihiro Hayakawa ◽  
Yiman Meng ◽  
Nobuhiko Hiramatsu ◽  
Ayumi Kasai ◽  
Jian Yao ◽  
...  
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Mesangial Cells ◽  
Ex Vivo ◽  
P38 Map Kinase ◽  
Paracrine Factors ◽  
Enhancer Element ◽  
Monocyte Chemoattractant Protein 1 ◽  
Isolated Glomeruli ◽  
Tnf Α

In this report, we describe that NF-κB is spontaneously activated in isolated, normal glomeruli. Ex vivo incubation of isolated rat glomeruli triggered expression of a NF-κB-dependent gene, monocyte chemoattractant protein-1 (MCP-1), in parallel with downregulation of IκBα and IκBβ proteins and activation of the p65 NF-κB subunit. The induction of MCP-1 was also observed in mesangial cells coincubated with isolated glomeruli or exposed to media conditioned by isolated glomeruli (GCM), which was abrogated by inhibition of NF-κB. The activation of NF-κB by glomerulus-derived factors was confirmed using reporter mesangial cells that produce secreted alkaline phosphatase (SEAP) under the control of the κB enhancer element. When the reporter cells were adoptively transferred into normal glomeruli, expression of SEAP mRNA and activity of SEAP were also upregulated in the explanted glomeruli. The molecular weight of factors responsible for activation of NF-κB was >50 kDa, and TNF-α was identified as one of glomerulus-derived activators. To examine upstream events involved, we focused on MAP kinases that are spontaneously activated in explanted glomeruli. Selective suppression of ERK or p38 MAP kinase significantly attenuated activation of NF-κB in mesangial cells triggered by coculture with isolated glomeruli. Interestingly, the suppressive effects by MAP kinase inhibitors were not observed in mesangial cells treated with GCM. These data suggested that NF-κB was spontaneously activated in explanted glomeruli via autocrine/paracrine factors including TNF-α and that the production of NF-κB activators by glomeruli was, at least in part, through MAP kinase pathways.

Endothelin signalling and regulation of protein kinases in glomerular mesangial cells

2002 ◽  
Vol 103 (s2002) ◽  
pp. 132S-136S ◽  
Author(s):  
Andrey SOROKIN ◽  
Marco FOSCHI ◽  
Michael J. DUNN
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Glomerular Mesangial Cells ◽  
Calcium Dependent ◽  
Mitogen Activated Protein

The molecular mechanisms of endothelin (ET)-dependent activation of extracellular signal-regulated kinase (ERK)and p38 mitogen-activated protein (MAP) kinase were studied in rat and human renal glomerular mesangial cells. ET-1 induced a rapid and transient activation of Ras in renal mesangial cells, which was dependent upon the formation of the Shc/Grb2/Sos1 signalling complex and resulted in transient ERK activation. We have observed that Pyk2, a calcium-dependent cytoplasmic tyrosine kinase, was expressed in human renal mesangial cells and was tyrosine phosphorylated after ET-1 treatment. ET-1-induced activation of p38 MAPK pathway (but not ERK pathway) was inhibited in human and in rat glomerular mesangial cells expressing dominant-negative form of Pyk2, suggesting the engagement of Pyk2 in ET-1-mediated activation of p38 MAP kinase cascade. Contractive responsiveness of renal mesangial cells was shown to depend on activation of the p38 MAP kinases. Thus, p38 MAP kinase stimulation could perhaps partially account for ET-1 contractive properties, whereas ET-1-induced cell proliferation occurs primarily via Ras-dependent activation of the ERK.

scholarly journals Essential Functions of Protein Tyrosine Phosphatases Ptp2 and Ptp3 and Rim11 Tyrosine Phosphorylation inSaccharomyces cerevisiaeMeiosis and Sporulation

2000 ◽  
Vol 11 (2) ◽  
pp. 663-676 ◽  
Author(s):  
Xiao-Li Zhan ◽  
Yulong Hong ◽  
Tianqing Zhu ◽  
Aaron P. Mitchell ◽  
Robert J. Deschenes ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Map Kinases ◽  
Early Stage ◽  
Protein Tyrosine Phosphatases ◽  
Homozygous Deletion ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Biochemical Processes ◽  
Tyrosine Phosphorylated Protein

Tyrosine phosphorylation plays a central role in eukaryotic signal transduction. In yeast, MAP kinase pathways are regulated by tyrosine phosphorylation, and it has been speculated that other biochemical processes may also be regulated by tyrosine phosphorylation. Previous genetic and biochemical studies demonstrate that protein tyrosine phosphatases (PTPases) negatively regulate yeast MAP kinases. Here we report that deletion of PTP2 and PTP3results in a sporulation defect, suggesting that tyrosine phosphorylation is involved in regulation of meiosis and sporulation. Deletion of PTP2 and PTP3 blocks cells at an early stage of sporulation before premeiotic DNA synthesis and induction of meiotic-specific genes. We observed that tyrosine phosphorylation of several proteins, including 52-, 43-, and 42-kDa proteins, was changed in ptp2Δptp3Δ homozygous deletion cells under sporulation conditions. The 42-kDa tyrosine-phosphorylated protein was identified as Mck1, which is a member of the GSK3 family of protein kinases and previously known to be phosphorylated on tyrosine. Mutation of MCK1 decreases sporulation efficiency, whereas mutation of RIM11, another GSK3 member, specifically abolishes sporulation; therefore, we investigated regulation of Rim11 by Tyr phosphorylation during sporulation. We demonstrated that Rim11 is phosphorylated on Tyr-199, and the Tyr phosphorylation is essential for its in vivo function, although Rim11 appears not to be directly regulated by Ptp2 and Ptp3. Biochemical characterizations indicate that tyrosine phosphorylation of Rim11 is essential for the activity of Rim11 to phosphorylate substrates. Our data demonstrate important roles of protein tyrosine phosphorylation in meiosis and sporulation

scholarly journals Protein Tyrosine Phosphatases in Neuroblastoma: Emerging Roles as Biomarkers and Therapeutic Targets

2021 ◽  
Vol 9 ◽  
Author(s):  
Caroline E. Nunes-Xavier ◽  
Laura Zaldumbide ◽  
Lorena Mosteiro ◽  
Ricardo López-Almaraz ◽  
Nagore García de Andoin ◽  
...  
Keyword(s):  
Cell Growth ◽  
Intracellular Signaling ◽  
Current Knowledge ◽  
Neuroblastoma Cell ◽  
Protein Tyrosine Phosphatases ◽  
Specific Protein ◽  
Neuroendocrine Cells ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Incidence And Mortality

Neuroblastoma is a type of cancer intimately related with early development and differentiation of neuroendocrine cells, and constitutes one of the pediatric cancers with higher incidence and mortality. Protein tyrosine phosphatases (PTPs) are key regulators of cell growth and differentiation by their direct effect on tyrosine dephosphorylation of specific protein substrates, exerting major functions in the modulation of intracellular signaling during neuron development in response to external cues driving cell proliferation, survival, and differentiation. We review here the current knowledge on the role of PTPs in neuroblastoma cell growth, survival, and differentiation. The potential of PTPs as biomarkers and molecular targets for inhibition in neuroblastoma therapies is discussed.

p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli

2005 ◽  
Vol 288 (6) ◽  
pp. F1133-F1143 ◽  
Author(s):  
Sahoko Hirano ◽  
Xiankui Sun ◽  
Cheryl A. DeGuzman ◽  
Richard F. Ransom ◽  
Kenneth R. McLeish ◽  
...  
Keyword(s):  
Map Kinase ◽  
P38 Mapk ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Mesangial Cells ◽  
Smooth Muscle Contraction ◽  
Environmental Pollutant ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Kinase Activation

The environmental pollutant cadmium affects human health, with the kidney being a primary target. In addition to proximal tubules, glomeruli and their contractile mesangial cells have also been identified as targets of cadmium nephrotoxicity. Glomerular contraction is thought to contribute to reduced glomerular filtration, a characteristic of cadmium nephrotoxicity. Because p38 MAPK/HSP25 signaling has been implicated in smooth muscle contraction, we examined its role in cadmium-induced contraction of mesangial cells. We report that exposure of mesangial cells to cadmium resulted in 1) cell contraction, 2) activation of MAP kinases, 3) increased HSP25 phosphorylation coincident with p38 MAP kinase activation, 4) sequential phosphorylation of the two phosphorylation sites of mouse HSP25 with Ser15 being phosphorylated before Ser86, 5) reduction of oligomeric size of HSP25, and 6) association of HSP25 with microfilaments. Exposure of isolated rat glomeruli to cadmium also resulted in contraction and increased HSP25 phosphorylation. The cadmium-induced responses were inhibited by the specific p38 MAP kinase inhibitor SB-203580, and cadmium-induced phosphorylation of HSP25 was inhibited by expression of a dominant-negative p38 MAP kinase mutant. These findings tentatively suggest that cadmium-induced nephrotoxicity results, in part, from glomerular contraction due to p38 MAP kinase/HSP25 signaling-dependent contraction of mesangial cells. With regard to the cellular action of HSP25, these data support a change in paradigm: in addition to its well-established cytoprotective function, HSP25 may also be involved in processes that ultimately lead to adverse effects, as is observed in the response of mesangial cells to cadmium.

Vanadium-induced HB-EGF expression in human lung fibroblasts is oxidant dependent and requires MAP kinases

2003 ◽  
Vol 284 (5) ◽  
pp. L774-L782 ◽  
Author(s):  
Jennifer L. Ingram ◽  
Annette B. Rice ◽  
Janine Santos ◽  
Bennett Van Houten ◽  
James C. Bonner
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Mrna Expression ◽  
Intracellular Signaling ◽  
Map Kinases ◽  
Human Lung ◽  
P38 Map Kinase ◽  
Lung Fibroblasts ◽  
Subsequent Increase ◽  
Human Lung Fibroblasts

Vanadium pentoxide (V2O5) is a transition metal derived from the burning of petrochemicals that causes airway fibrosis and remodeling. Vanadium compounds activate many intracellular signaling pathways via the generation of hydrogen peroxide (H2O2) or other reactive oxygen species. In this study, we investigated the regulation of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in human lung fibroblasts after V2O5 treatment. V2O5-induced HB-EGF mRNA expression was abolished by N-acetyl-l-cysteine, suggesting an oxidant-mediated effect. Exogenous H2O2 (>10 μM) mimicked the effect of V2O5 in upregulating HB-EGF expression. Fibroblasts spontaneously released low levels of H2O2 (1–2 μM), and the addition of V2O5 depleted the endogenous H2O2 pool within minutes. V2O5 caused a subsequent increase of H2O2 into the culture medium at 12 h. However, the burst of V2O5-induced H2O2 occurred after V2O5-induced HB-EGF mRNA expression at 3 h, indicating that the V2O5-stimulated H2O2 burst did not mediate HB-EGF expression. Either V2O5 or H2O2activated ERK-1/2 and p38 MAP kinase. Inhibitors of the ERK-1/2 pathway (PD-98059) or p38 MAP kinase (SB-203580) significantly reduced either V2O5- or H2O2-induced HB-EGF expression. These data indicate that vanadium upregulates HB-EGF via ERK and p38 MAP kinases. The induction of HB-EGF is not related to a burst of H2O2 in V2O5treated cells, yet the action of V2O5 in upregulating HB-EGF is oxidant dependent and could be due to the reaction of V2O5 with endogenous H2O2.

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