title: Haematopoietic progenitor cells utilise conventional PKC to suppress PKB/Akt activity in response to c-Kit stimulation.
abstract: Receptor tyrosine kinase (RTK) c-Kit signalling is crucial for the proliferation, survival and differentiation of haematopoietic stem cells (HSCs). To further understand the mechanisms underlying these events we explored how the downstream mediators interact. The present study investigated the function of conventional protein kinase Cs (c-PKC) in c-Kit mediated signalling pathways in HSC-like cell lines. This analysis supported earlier findings, that steel factor (SF) activates c-PKC, extracellular signal-regulated kinase (Erk) and protein kinase B (PKB). The present results were consistent with an important role of c-PKC in the positive activation of Erk and for proliferation. Further, it was observed that c-PKC negatively regulated PKB activity upon SF stimulation, indicating that c-PKC acts as a suppressor of c-Kit signalling. Finally, these observations were extended to show that c-PKC mediated the phosphorylation of the endogenous c-Kit receptor on serine 746, resulting in decreased overall tyrosine phosphorylation of c-Kit upon SF stimulation. This report showed that this specific feedback mechanism of c-PKC mediated phosphorylation of the c-Kit receptor has consequences for both proliferation and survival of HSC-like cell lines.
authors.affiliation: Department of Medical Biosciences/Pathology, Umeå University, Umeå, Sweden.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Edling
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.forename: Leif
authors.initials: L
authors.lastname: Carlsson
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Palmer
authors.forename: Bengt
authors.initials: B
authors.lastname: Hallberg
mesh_terms: D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases