Advanced

Increased Kit/SCF receptor induced mitogenicity but abolished cell motility after inhibition of protein kinase C

Blume-Jensen, Peter; Siegbahn, Agneta; Stabel, Silvia; Heldin, Carl-Henrik and Rönnstrand, Lars LU (1993) In EMBO Journal 12(11). p.4199-4209
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
@article{1585a467-b048-4ee9-acc2-ae5d0822cc87,
  abstract     = {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.},
  author       = {Blume-Jensen, Peter and Siegbahn, Agneta and Stabel, Silvia and Heldin, Carl-Henrik and Rönnstrand, Lars},
  issn         = {1460-2075},
  keyword      = {Vascular/drug effects/enzymology/*growth & development
Hematopoietic Cell Growth Factors/pharmacology
Humans
*Naphthalenes
Phosphorylation
Polycyclic Compounds/pharmacology
Protein Kinase C/antagonists & inhibitors/*metabolism
Proto-Oncogene Proteins/*metabolism
Proto-Oncogene Proteins c-kit
Receptor Protein-Tyrosine Kinases/*metabolism
Receptors,Cultured
Chemotaxis
Endothelium,Animals
Aorta/cytology
Cell Division/drug effects
*Cell Movement/drug effects
Cells,Colony-Stimulating Factor/*metabolism
Serine/metabolism
Stem Cell Factor
Swine},
  language     = {eng},
  number       = {11},
  pages        = {4199--4209},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {Increased Kit/SCF receptor induced mitogenicity but abolished cell motility after inhibition of protein kinase C},
  volume       = {12},
  year         = {1993},
}