PKCdelta plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant.
The Kit receptor tyrosine kinase is critical for normal hematopoiesis. Mutation of the aspartic acid residue encoded by codon 816 of human c-kit or codon 814 of the murine gene results in an oncogenic form of Kit. Here we investigate the role of protein kinase Cdelta (PKCdelta) in responses mediated by wild-type murine Kit and the D814Y mutant in a murine mast cell-like line. PKCdelta is activated after wild-type (WT) Kit binds stem cell factor (SCF), is constitutively active in cells expressing the Kit catalytic domain mutant, and coprecipitates with both forms of Kit. Inhibition of PKCdelta had opposite effects on growth mediated by wild-type and mutant Kit. Both rottlerin and a dominant-negative PKCdelta construct inhibited the growth of cells expressing mutant Kit, while SCF-induced growth of cells expressing wild-type Kit was not inhibited. Further, overexpression of PKCdelta inhibited growth of cells expressing wild-type Kit and enhanced growth of cells expressing the Kit mutant. These data demonstrate that PKCdelta contributes to factor-independent growth of cells expressing the D814Y mutant, but negatively regulates SCF-induced growth of cells expressing wild-type Kit. This is the first demonstration that PKCdelta has different functions in cells expressing normal versus oncogenic forms of a receptor.
Jelacic
Tanya
T
Basic Research Laboratory, Center for Cancer Research, Bldg 469, Rm 205, National Cancer Institute-Frederick, Frederick, MD 21702, USA. t_jelacic_obreiter@ncifcrf.gov
Linnekin
Diana
D
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D051745:Protein Kinase C-delta; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D050796:STAT3 Transcription Factor; D019089:Stem Cell Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019089:Stem Cell Factor; D015534:Trans-Activators; C497259:Prkcd protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D011493:Protein Kinase C; D051745:Protein Kinase C-delta