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The Inhibitory γ Subunit of the Type 6 Retinal Cyclic Guanosine Monophosphate Phosphodiesterase Is a Novel Intermediate Regulating p42/p44 Mitogen-activated Protein Kinase Signaling in Human Embryonic Kidney 293 Cells
- Source :
- Journal of Biological Chemistry. 276:37802-37808
- Publication Year :
- 2001
- Publisher :
- American Society for Biochemistry & Molecular Biology (ASBMB), 2001.
-
Abstract
- The inhibitory gamma subunits of the retinal rod and cone photoreceptor type 6 retinal cyclic guanosine monophosphate phosphodiesterase (PDEgamma) are expressed in non-retinal tissues. Here, we show that PDEgamma interacts with the G-protein-coupled receptor kinase 2 signaling system to regulate the epidermal growth factor- and thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase in human embryonic kidney 293 cells. This is based upon several lines of evidence. First, the transfection of cells with an antisense rod PDEgamma plasmid construct, which reduced endogenous rod PDEgamma expression, ablated the epidermal growth factor- and thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase. Second, the transfection of cells with recombinant rod or cone PDEgamma and/or G-protein-coupled receptor kinase 2 increased the stimulation of p42/p44 mitogen-activated protein kinase by epidermal growth factor or thrombin. In contrast, a G-protein-coupled receptor kinase 2 phosphorylation-resistant rod PDEgamma mutant failed to increase the epidermal growth factor- or thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase and, in fact, functioned as a dominant negative. Thrombin also stimulated the association of endogenous rod PDEgamma with dynamin II, which was increased in cells transfected with rod PDEgamma or G-protein-coupled receptor kinase 2. Dynamin II plays a critical role in regulating endocytosis of receptor signal complexes required for activation of p42/p44 mitogen-activated protein kinase. Therefore, PDEgamma may have an important role in promoting endocytosis of receptor signal complexes leading to the activation of p42/p44 mitogen-activated protein kinase. We conclude that PDEgamma is an entirely novel intermediate regulating mitogenic signaling from both receptor tyrosine kinase and G-protein-coupled receptors in human embryonic kidney 293 cells.
- Subjects :
- Dynamins
endocrine system
Blotting, Western
Molecular Sequence Data
Mitogen-activated protein kinase kinase
Kidney
environment and public health
Biochemistry
Tropomyosin receptor kinase C
Retina
Receptor tyrosine kinase
Cell Line
GTP Phosphohydrolases
3',5'-Cyclic-GMP Phosphodiesterases
Epidermal growth factor
Humans
ASK1
Phosphorylation
Protein kinase A
Molecular Biology
DNA Primers
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Base Sequence
Epidermal Growth Factor
biology
MAP kinase kinase kinase
Cell Biology
Recombinant Proteins
Cell biology
Enzyme Activation
biology.protein
Cyclin-dependent kinase 9
Mitogen-Activated Protein Kinases
biological phenomena, cell phenomena, and immunity
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 276
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....23dd7f62ca64081f8efa6ffa0c6a1d66