ERK1/2‐driven and MKP‐mediated inhibition of EGF‐induced ERK5 signaling in human proximal tubular cells

Sarközi, Rita; Miller, Bradley; Pollack, Verena; Feifel, Elisabeth; Mayer, Gert; Sorokin, Andrey; Schramek, Herbert

doi:10.1002/jcp.20909

Cited by 32 publications

(27 citation statements)

References 49 publications

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“…With respect to HK-2 cell proliferation, both EGF and BPE have been reported to act as essential mitogens for these cells (46,47). However, in the present study we observed that HK-2 cells proliferate even in the absence of growth supplements such as FBS, recombinant EGF or BPE (Fig.…”

Section: Osm-induced Expression Of Collagen Type I and Vimentin In Hkcontrasting

confidence: 54%

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Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling

Pollack¹,

Sarközi²,

Bánki³

et al. 2007

American Journal of Physiology-Renal Physiology

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Growing evidence suggests that a proportion of interstitial myofibroblasts detected during renal tubulointerstitial fibrosis originates from tubular epithelial cells by a process called epithelial-mesenchymal transition (EMT). The IL-6-type cytokine oncostatin M (OSM) has been recently implicated in the induction of EMT. We investigated OSM effects on the expression of both cell-cell contact proteins and mesenchymal markers and studied OSM-induced intracellular signaling mechanisms associated with these events in human proximal tubular cells. Human recombinant OSM attenuated the expression of N-cadherin, E-cadherin, and claudin-2 in human kidney-2 (HK-2) cells associated with the induction of HK-2 cell scattering in 3D collagen matrices. Conversely, expression of collagen type I, vimentin, and S100A4 was induced by OSM. OSM-stimulated cell scattering was inhibited by antibodies against gp130. Besides inducing phosphorylation of Stat1 and Stat3, OSM led to a strong concentration-and time-dependent phosphorylation of the mitogen-activated protein kinases ERK1, ERK2, and ERK5. MEK1/2 inhibitor U0126 (10 M) blocked basal and OSM-induced ERK1/2 phosphorylation but not phosphorylation of either ERK5 or Stat1/3. Both synthetic MEK1/2 inhibitors U0126 and Cl-1040, when used at concentrations which inhibit ERK1/2 phosphorylation but not ERK5 phosphorylation, restored N-cadherin expression in the presence of OSM, inhibited basal claudin-2 expression, but did not affect either basal or OSM-inhibited E-cadherin expression or OSM-induced expression of collagen type I and vimentin. These results suggest that in human proximal tubular cells ERK1/2 signaling represents an important component of OSM's inhibitory effect on N-cadherin expression. Furthermore, functional ERK1/2 signaling is necessary for basal claudin-2 expression.

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Section: Osm-induced Expression Of Collagen Type I and Vimentin In Hkcontrasting

confidence: 54%

“…Human kidney 2 (HK-2) cells were cultured in keratinocyte-serum-free medium (KSFM) containing 10% FBS, 5 ng/ml recombinant epidermal growth factor (rEGF), 0.05 mg/ml BPE, 100 U/ml penicillin, and 100 g/ml streptomycin (46,47). The cells were grown at 37°C in a humidified 5% CO 2 atmosphere and split at a 1:5 ratio once a week.…”

Section: Methodsmentioning

confidence: 99%

Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling

Pollack¹,

Sarközi²,

Bánki³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…[8][9][10] The cells (passages [20][21][22][23][24][25][26][27][28][29][30] were grown at 371C in a humidified 5% CO 2 atmosphere, and split at a 1:10 ratio, once a week. After growth to a subconfluent state, cells were washed once, made quiescent by incubation in serum-and supplementfree medium for 48 h, and then used for experiments.…”

Section: Cell Culturementioning

confidence: 99%

“…9 RNA quantity was estimated by spectrophotometric analysis. Reverse transcription was carried out in 20 ml volume using 2 mg total RNA, 1 mM random hexanucleotides as primer (Roche Diagnostics, Indianapolis, IN, USA), and Omniscript Reverse Transcriptase (Qiagen) according to the manufacturer's instructions.…”

Section: Rna Isolation and Real-time Pcr Analysismentioning

confidence: 99%

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Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells

Schramek

Sarközi

Lauterberg

et al. 2009

Laboratory Investigation

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Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins with large extracellular domains that interact with class 3 semaphorins, vascular endothelial growth factor (VEGF) family members, and ligands, such as hepatocyte growth factor, platelet-derived growth factor BB, transforming growth factor-b1 (TGF-b1), and fibroblast growth factor2 (FGF2). Neuropilins (NRPs) have been implicated in tumor growth and vascularization, as novel mediators of the primary immune response and in regeneration and repair; however, their role in renal pathophysiology is largely unknown. Here, we report upregulation of tubular and interstitial NRP2 protein expression in patients with focal segmental glomerulosclerosis (FSGS). In an additional cohort of patients with minimal change disease (MCD), membranous nephropathy (MN), and FSGS, elevated NRP2 mRNA expression in kidney biopsies inversely correlated with estimated glomerular filtration rate (eGFR) at the time of biopsy. Furthermore, upregulation of NRP2 mRNA correlated with post-bioptic decline of kidney function. Expression of NRP1 and NRP2 in human proximal tubular cells (PTCs) was differentially affected after stimulation with TGF-b1, interleukin-1b (IL-1b), and oncostatin M (OSM). Although the pro-fibrotic mediators, TGF-b1 and IL-1b, induced upregulation of NRP2 expression but downregulation of NRP1 expression, OSM stimulated the expression of both NRP1 and NRP2. Basal and OSM-induced NRP1 mRNA expression, as well as TGF-b1-induced NRP2 mRNA and protein expression were partially mediated by MEK1/2-ERK1/2 signaling. This is the first report suggesting a differential role of NRP1 and NRP2 in renal fibrogenesis, and TGF-b1, IL-1b, and OSM represent the first ligands known to stimulate NRP2 expression in mammalian cells.

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Dual‐specificity phosphatase 6 deletion protects the colonic epithelium against inflammation and promotes both proliferation and tumorigenesis

Beaudry

Langlois

Montagne

et al. 2018

Journal Cellular Physiology

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The Ras/mitogen‐activated protein kinase (MAPK) pathway controls fundamental cellular processes such as proliferation, differentiation, and apoptosis. The dual‐specificity phosphatase 6 (DUSP6) regulates cytoplasmic MAPK signaling by dephosphorylating and inactivating extracellular signal‐regulated kinase (ERK1/2) MAPK. To determine the role of DUSP6 in the maintenance of intestinal homeostasis, we characterized the intestinal epithelial phenotype of Dusp6 knockout (KO) mice under normal, oncogenic, and proinflammatory conditions. Our results show that loss of Dusp6 increased crypt depth and epithelial cell proliferation without altering colonic architecture. Crypt regeneration capacity was also enhanced, as revealed by ex vivo Dusp6 KO organoid cultures. Additionally, loss of Dusp6 induced goblet cell expansion without affecting enteroendocrine and absorptive cell differentiation. Our data also demonstrate that Dusp6 KO mice were protected from acute dextran sulfate sodium‐induced colitis, as opposed to wild‐type mice. In addition, Dusp6 gene deletion markedly enhanced tumor load in Apc Min/+ mice. Decreased DUSP6 expression by RNA interference in HT29 colorectal cancer cells enhanced ERK1/2 activation levels and promoted both anchorage‐independent growth in soft agar as well as invasion through Matrigel. Finally, DUSP6 mRNA expression in human colorectal tumors was decreased in advanced stage tumors compared with paired normal tissues. These results demonstrate that DUSP6 phosphatase, by controlling ERK1/2 activation, regulates colonic inflammatory responses, and protects the intestinal epithelium against oncogenic stress.

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ERK1/2‐driven and MKP‐mediated inhibition of EGF‐induced ERK5 signaling in human proximal tubular cells

Cited by 32 publications

References 49 publications

Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling

Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling

Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells

Dual‐specificity phosphatase 6 deletion protects the colonic epithelium against inflammation and promotes both proliferation and tumorigenesis

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