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

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Author

  • Peter Blume-Jensen
  • Lars Rönnstrand
  • Ivan Gout
  • Michael D. Waterfield
  • Carl-Henrik Heldin

Summary, in English

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.

Publishing year

1994

Language

English

Pages

21793-21802

Publication/Series

Journal of Biological Chemistry

Volume

269

Issue

34

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Medicinal Chemistry

Keywords

  • 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

Status

Published

ISBN/ISSN/Other

  • ISSN: 1083-351X