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ERK1/2-driven and MKP-mediated inhibition of EGF-induced ERK5 signaling in human proximal tubular cells.
- Source :
-
Journal of cellular physiology [J Cell Physiol] 2007 Apr; Vol. 211 (1), pp. 88-100. - Publication Year :
- 2007
-
Abstract
- The MEK1-ERK1/2 signaling pathway has been implicated in the regulation of renal epithelial cell proliferation, epithelial-to-mesenchymal transition and the induction of an invasive cell phenotype. Much less information is available about the MEK5-ERK5 module and its role in renal epithelial cell proliferation and differentiation. In the present study we have investigated the regulation of these two families of extracellular signal-regulated kinases in epidermal growth factor (EGF)-stimulated human kidney-2 (HK-2) cells and a possible interaction between ERK1/2 and ERK5. Here we report that 5 ng/ml EGF led to a strong stimulation of HK-2 cell proliferation, which was largely U0126-sensitive. Both synthetic MEK1/2 inhibitors U0126 and Cl-1040, when used at 10 and 1 microM, respectively, inhibited basal and EGF-induced ERK1/2 phosphorylation but not ERK5 phosphorylation. Long-term inhibition of MEK1/2-ERK1/2 signaling and/or vanadate-sensitive protein phosphatases enhanced and prolonged EGF-induced ERK5 phosphorylation, while transient expression of an adenoviral constitutively active MEK1 (Ad-caMEK1) construct completely blocked EGF-induced ERK5 phosphorylation. Expression of Ad-caMEK1 in HK-2 cells resulted in the upregulation of the dual-specificity phosphatases MKP-3/DUSP6, MKP-1/DUSP1, and DUSP5. The EGF-mediated time-dependent induction of MKP-3, MKP-1 and DUSP5 mRNA levels was U0126-sensitive at a concentration, which blocked EGF-mediated ERK1/2 phosphorylation but not ERK5 phosphorylation. Furthermore, U0126 inhibited EGF-induced MKP-3 and MKP-1 protein expression. Both MKP-3 and MKP-1 co-immunoprecipitated with ERK5 in unstimulated as well as in EGF-stimulated HK-2 cells. These results suggest the existence of an ERK1/2-driven negative feed-back regulation of ERK5 signaling in EGF-stimulated HK-2 cells, which is mediated by MKP-3, DUSP5 and/or MKP-1.<br /> ((c) 2006 Wiley-Liss, Inc.)
- Subjects :
- Benzamides pharmacology
Butadienes pharmacology
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Cell Proliferation drug effects
Cells, Cultured
Dual Specificity Phosphatase 1
Dual Specificity Phosphatase 6
Dual-Specificity Phosphatases
Enzyme Activation drug effects
Enzyme Induction drug effects
Humans
Immediate-Early Proteins genetics
Immediate-Early Proteins metabolism
Isoenzymes genetics
Isoenzymes metabolism
Kidney Tubules, Proximal cytology
Kidney Tubules, Proximal drug effects
MAP Kinase Kinase 1 metabolism
Nitriles pharmacology
Phosphoprotein Phosphatases genetics
Phosphoprotein Phosphatases metabolism
Phosphorylation drug effects
Protein Phosphatase 1
Protein Tyrosine Phosphatases genetics
RNA, Messenger genetics
RNA, Messenger metabolism
Time Factors
Vanadates pharmacology
Epidermal Growth Factor pharmacology
Kidney Tubules, Proximal enzymology
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Mitogen-Activated Protein Kinase 7 metabolism
Protein Tyrosine Phosphatases metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9541
- Volume :
- 211
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of cellular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 17131384
- Full Text :
- https://doi.org/10.1002/jcp.20909