title: Distinct signalling pathways for mutated KIT(V560G) and KIT(D816V) in mastocytosis.
abstract: BACKGROUND
  The activating mutations KIT(V560G) and KIT(D816V) are associated with mastocytosis. Thus, identifying and inhibiting the signalling pathways associated with mutated KIT gene offers a potentially important strategy for the treatment of mastocytosis.
  
  
  OBJECTIVE
  To correlate KIT mutations with specific signalling pathways in human mast-cell lines using pathway inhibitors.
  
  
  METHODS
  Human mast-cell (HMC) lines expressing KIT(V560G) (the cell line HMC-1) and KIT(V560G and D816V) (HMC-1.2) were treated with specific signalling pathway inhibitors for 1-5 days, and the inhibitory effects on growth were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell-proliferation assay, western blotting and flow cytometry.
  
  
  RESULTS
  Growth inhibitory assays and western blot analyses showed that the Janus kinase 3/signal transducer and activator of transcription (JAK3/STAT) pathway is the preferential signalling pathway for KIT(V560G), whereas the mechanistic target of rapamycin complex 1/4E-binding protein 1 (mTORC1/4E-BP1) pathway is preferentially linked to KIT(D816V). Inhibition of these critical signalling pathways results in programmed cell death.
  
  
  CONCLUSIONS
  KIT(V560G) and KIT(D816V) use different signalling pathways that promote mast-cell growth. Inhibitors of these specific pathways might be effective in treating mastocytosis.
authors.affiliation: Department of Dermatology, Rush University Medical Center, Chicago, IL, USA. ichan@rush.edu
authors.forename: I J
authors.initials: IJ
authors.lastname: Chan
authors.forename: S
authors.initials: S
authors.lastname: Kasprowicz
authors.forename: M D
authors.initials: MD
authors.lastname: Tharp
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D008415:Mastocytosis / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit