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

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 ; Rönnstrand, Lars ; Gout, Ivan ; Waterfield, Michael D. and Heldin, Carl-Henrik
• publishing date: 1994
• type: Contribution to journal
• publication status: published
• subject: 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
• in: Journal of Biological Chemistry
• volume: 269
• issue: 34
• pages: 21793 - 21802
• publisher: American Society for Biochemistry and Molecular Biology
• external identifiers: scopus:0027965243
• ISSN: 1083-351X
• language: English
• LU publication?: no
• additional info: The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
• id: c93356e0-8094-4688-aa8d-de9c671bd0bb (old id 1784103)
• alternative location: http://www.jbc.org/content/269/34/21793.short
• date added to LUP: 2016-04-04 08:41:37
• date last changed: 2021-01-03 05:03:52