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

Författare

  • Peter Blume-Jensen
  • Agneta Siegbahn
  • Silvia Stabel
  • Carl-Henrik Heldin
  • Lars Rönnstrand

Summary, in English

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.

Publiceringsår

1993

Språk

Engelska

Sidor

4199-4209

Publikation/Tidskrift/Serie

EMBO Journal

Volym

12

Issue

11

Dokumenttyp

Artikel i tidskrift

Förlag

Oxford University Press

Ämne

  • Medicinal Chemistry

Nyckelord

  • Vascular/drug effects/enzymology/*growth & developmentHematopoietic Cell Growth Factors/pharmacologyHumans*NaphthalenesPhosphorylationPolycyclic Compounds/pharmacologyProtein Kinase C/antagonists & inhibitors/*metabolismProto-Oncogene Proteins/*metabolismProto-Oncogene Proteins c-kitReceptor Protein-Tyrosine Kinases/*metabolismReceptors
  • CulturedChemotaxisEndothelium
  • AnimalsAorta/cytologyCell Division/drug effects*Cell Movement/drug effectsCells
  • Colony-Stimulating Factor/*metabolismSerine/metabolismStem Cell FactorSwine

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1460-2075