Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis.
The proto-oncogene c-kit is allelic with the murine white spotting (W) locus and encodes a transmembrane protein tyrosine kinase that is structurally related to the receptors for platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1). Recently the ligand for the c-kit product, stem cell factor (SCF), was identified in both transmembrane and soluble forms. In order to examine the mechanism for receptor activation by SCF and biological properties of the activated c-kit product, we transfected the wild-type human c-kit cDNA into porcine aortic endothelial cells. We found that the receptor was down-regulated and transmitted a mitogenic signal in response to stimulation with soluble SCF. We also demonstrate that SCF induces dimerization of the c-kit product in intact cells, and that dimerization of the receptor is correlated with activation of its kinase. Activation of the c-kit product by SCF was found to induce circular actin reorganization indistinguishable from that mediated by the PDGF beta-receptor in response to PDGF-BB. Furthermore, soluble SCF was a potent chemotactic agent for cells expressing the c-kit product, a property which might be of importance during embryonic development.
Blume-Jensen
P
P
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Claesson-Welsh
L
L
Siegbahn
A
A
Zsebo
K M
KM
Westermark
B
B
Heldin
C H
CH
D000199:Actins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002633:Chemotaxis; D003432:Cross-Linking Reagents; D003599:Cytoskeleton / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor; D013552:Swine; D013936:Thymidine / Q000378:metabolism
D000199:Actins; D003432:Cross-Linking Reagents; D016298:Hematopoietic Cell Growth Factors; D008024:Ligands; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D013936:Thymidine