Increased Kit/SCF receptor induced mitogenicity but abolished cell motility after inhibition of protein kinase C.
The product of the c-kit proto-oncogene, denoted Kit/SCF-R, encodes a tyrosine kinase receptor for stem cell factor (SCF). Kit/SCF-R induces proliferation, differentiation or migration of cells within the hematopoietic, gametogenic and melanogenic lineages at different developmental stages. We report here that protein kinase C (PKC) mediates phosphorylation of Kit/SCF-R on serine residues in response to SCF or PMA in intact cells. The phosphorylation inhibits SCF-induced tyrosine autophosphorylation of Kit/SCF-R. In vitro studies showed that PKC phosphorylated the Kit/SCF-R directly on serine residues and inhibited autophosphorylation of Kit/SCF-R, as well as its kinase activity towards an exogenous substrate. The PKC-induced phosphorylation did not affect Kit/SCF-R ligand binding affinity. Inhibition of PKC led to increased SCF-induced tyrosine autophosphorylation, as well as increased SCF-induced mitogenicity. In contrast, PKC was necessary for SCF-induced motility responses, including actin reorganization and chemotaxis. Our data suggest that PKC is involved in a negative feedback loop which regulates the Kit/SCF-R and that the activity of PKC determines whether the effect of SCF will be preferentially mitogenic or motogenic.
Blume-Jensen
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P
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.
Siegbahn
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A
Stabel
S
S
Heldin
C H
CH
Rönnstrand
L
L
D000818:Animals; D001011:Aorta / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006801:Humans; D009281:Naphthalenes; D010766:Phosphorylation; D011083:Polycyclic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D016184:Receptors, Colony-Stimulating Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D019089:Stem Cell Factor; D013552:Swine
D016298:Hematopoietic Cell Growth Factors; C000715470:MAS1 protein, human; D009281:Naphthalenes; D011083:Polycyclic Compounds; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D019089:Stem Cell Factor; D012694:Serine; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D011493:Protein Kinase C; C058819:calphostin C