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Modulation of Kit/stem cell factor receptor-induced signaling by protein kinase C

Blume-Jensen, Peter; Rönnstrand, Lars LU ; Gout, Ivan; Waterfield, Michael D. and Heldin, Carl-Henrik (1994) In Journal of Biological Chemistry 269(34). p.21793-21802
Abstract
The Kit/stem cell factor receptor (Kit/SCF-R) is a transmembrane tyrosine kinase receptor of importance for the normal development of hemopoietic cells, melanoblasts, and germ cells. We recently reported that protein kinase C (PKC) is involved in a negative feedback loop regulating the Kit/SCF-R by direct phosphorylation on serine residues in the receptor. Inhibition of PKC led to increased SCF-induced tyrosine kinase activity and mitogenicity, but PKC was necessary for SCF-induced motility. In this report we have further examined the modulatory role of PKC on SCF-induced signaling. The ligand-activated Kit/SCF-R associated weakly with GRB2 and induced only little tyrosine phosphorylation of phospholipase C-gamma in porcine aortic... (More)
The Kit/stem cell factor receptor (Kit/SCF-R) is a transmembrane tyrosine kinase receptor of importance for the normal development of hemopoietic cells, melanoblasts, and germ cells. We recently reported that protein kinase C (PKC) is involved in a negative feedback loop regulating the Kit/SCF-R by direct phosphorylation on serine residues in the receptor. Inhibition of PKC led to increased SCF-induced tyrosine kinase activity and mitogenicity, but PKC was necessary for SCF-induced motility. In this report we have further examined the modulatory role of PKC on SCF-induced signaling. The ligand-activated Kit/SCF-R associated weakly with GRB2 and induced only little tyrosine phosphorylation of phospholipase C-gamma in porcine aortic endothelial cells transfected with Kit/SCF-R. In contrast, the SCF-stimulated Kit/SCF-R associated efficiently with, and induced tyrosine phosphorylation of, the p85 alpha regulatory subunit of phosphatidyl inositide-3'-kinase (PI-3'-kinase). Both receptor association and tyrosine phosphorylation of p85 alpha were increased after inhibition of PKC, while its serine phosphorylation was decreased. Concomitantly, the specific activity of receptor-associated PI-3'-kinase activity was increased. Inhibition of PI-3'-kinase with wortmannin inhibited SCF-induced mitogenicity. SCF-induced phosphorylation of Raf-1 and activation of ERK2 still occurred after PKC inhibition but was not increased. In conclusion, SCF-induced PI-3'-kinase activation paralleled the increased SCF-induced mitogenicity after inhibition of PKC. (Less)
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@article{c93356e0-8094-4688-aa8d-de9c671bd0bb,
  abstract     = {The Kit/stem cell factor receptor (Kit/SCF-R) is a transmembrane tyrosine kinase receptor of importance for the normal development of hemopoietic cells, melanoblasts, and germ cells. We recently reported that protein kinase C (PKC) is involved in a negative feedback loop regulating the Kit/SCF-R by direct phosphorylation on serine residues in the receptor. Inhibition of PKC led to increased SCF-induced tyrosine kinase activity and mitogenicity, but PKC was necessary for SCF-induced motility. In this report we have further examined the modulatory role of PKC on SCF-induced signaling. The ligand-activated Kit/SCF-R associated weakly with GRB2 and induced only little tyrosine phosphorylation of phospholipase C-gamma in porcine aortic endothelial cells transfected with Kit/SCF-R. In contrast, the SCF-stimulated Kit/SCF-R associated efficiently with, and induced tyrosine phosphorylation of, the p85 alpha regulatory subunit of phosphatidyl inositide-3'-kinase (PI-3'-kinase). Both receptor association and tyrosine phosphorylation of p85 alpha were increased after inhibition of PKC, while its serine phosphorylation was decreased. Concomitantly, the specific activity of receptor-associated PI-3'-kinase activity was increased. Inhibition of PI-3'-kinase with wortmannin inhibited SCF-induced mitogenicity. SCF-induced phosphorylation of Raf-1 and activation of ERK2 still occurred after PKC inhibition but was not increased. In conclusion, SCF-induced PI-3'-kinase activation paralleled the increased SCF-induced mitogenicity after inhibition of PKC.},
  author       = {Blume-Jensen, Peter and Rönnstrand, Lars and Gout, Ivan and Waterfield, Michael D. and Heldin, Carl-Henrik},
  issn         = {1083-351X},
  keyword      = {Signal Transducing
Androstadienes/pharmacology
Animals
Aorta/anatomy & histology
Endothelium,Colony-Stimulating Factor/genetics/*metabolism
Recombinant Proteins/metabolism
*Signal Transduction
Stem Cell Factor
Swine
Transfection
Type C Phospholipases/metabolism
Tyrosine/metabolism,*Adaptor Proteins,Vascular/cytology
GRB2 Adaptor Protein
Hematopoietic Cell Growth Factors/metabolism
Isoenzymes/metabolism
Mitogen-Activated Protein Kinase 1
Phosphatidylinositol 3-Kinases
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor)/metabolism
Protein Kinase C/*metabolism
Protein-Serine-Threonine Kinases/metabolism
Protein-Tyrosine Kinases/metabolism
Proteins/metabolism
Proto-Oncogene Proteins/genetics/*metabolism
Proto-Oncogene Proteins c-kit
Proto-Oncogene Proteins c-raf
Receptor Protein-Tyrosine Kinases/genetics/*metabolism
Receptors},
  language     = {eng},
  number       = {34},
  pages        = {21793--21802},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Modulation of Kit/stem cell factor receptor-induced signaling by protein kinase C},
  volume       = {269},
  year         = {1994},
}