A novel MPL point mutation resulting in thrombopoietin-independent activation

Leukemia. 2002 Aug;16(8):1500-6. doi: 10.1038/sj.leu.2402554.

Abstract

Thrombopoietin (TPO) and its receptor (MPL) are important regulators of megakaryopoiesis. MPL belongs to a cytokine receptor superfamily. To date, all constitutively active MPL mutants have been artificially constructed with amino acid substitutions in the transmembrane domain or extracellular domain of the protein, and they activate signal transduction pathways in Ba/F3 cells that can also be activated by the normal MPL. In this paper, we report a novel spontaneously occurring mutation of MPL, with an amino acid substitution of Trp(508) to Ser(508) in the intracellular domain of MPL, that induces the factor-independent growth of Ba/F3 cells. Examination of intracellular signaling pathways demonstrated that the mutant MPL protein constitutively activates three distinct signaling pathways, SHC-Ras-Raf-MAPK/JNK, JAK-STAT, and PI3K-Akt-Bad.

Publication types

  • Comparative Study

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Amino Acid Substitution*
  • Animals
  • Carrier Proteins / metabolism
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Janus Kinase 2
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred BALB C
  • Milk Proteins*
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation, Missense*
  • Neoplasm Proteins*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Point Mutation*
  • Protein Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / metabolism
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf / metabolism
  • Receptors, Cytokine*
  • Receptors, Thrombopoietin
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / physiology
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Shc Signaling Adaptor Proteins
  • Signal Transduction / physiology*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Structure-Activity Relationship
  • Thrombopoietin / pharmacology*
  • Trans-Activators / metabolism
  • Transfection
  • bcl-Associated Death Protein
  • ras GTPase-Activating Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • BAD protein, human
  • Bad protein, mouse
  • Carrier Proteins
  • DNA-Binding Proteins
  • Milk Proteins
  • Neoplasm Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Cytokine
  • Receptors, Thrombopoietin
  • Recombinant Fusion Proteins
  • SHC1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Stat3 protein, mouse
  • Trans-Activators
  • bcl-Associated Death Protein
  • ras GTPase-Activating Proteins
  • MPL protein, human
  • Thrombopoietin
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Jak2 protein, mouse
  • Janus Kinase 2
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases