Mitogenic signaling and inhibition of apoptosis via the erythropoietin receptor Box-1 domain.

Academic Article

Abstract

  • Studies of proliferative signaling via type 1 cytokine receptors have revealed a three-step activation mechanism. Cytokine-induced receptor dimerization mediates the trans-phosphorylation of Jak kinases, Jaks phosphorylate receptors at tyrosine sites, and SH2 domain-encoding effectors then are recruited to these sites. Signaling factors that associate with activated erythropoietin (Epo) receptor complexes include phospholipase C-gamma, phosphatidylinositol 3-kinase, SHIP, Shc, Grb2, Cbl, Crk-l, HCP, Syp, and STAT5. While at least certain of these factors modulate proliferative signaling, mutated Epo receptor forms lacking Tyr(P) sites retain substantial mitogenic activity. Presently we show that a highly truncated Epo receptor form that retains box-1, yet lacks the conserved box-2 domain (and all Tyr(P) sites) nonetheless effectively promotes mitogenesis, survival, and Myc and Pim-1 expression. In addition, mitogenesis and Myc expression are shown to be supported by a direct Epo receptor-Jak2 kinase domain chimera. Thus, Epo-dependent mitogenesis and inhibition of apoptosis each depend critically upon only the Epo receptor box-1 domain, with no essential role exerted in these response pathways by the box-2 domain.
  • Authors

  • Joneja, B
  • Wojchowski, Don
  • Status

    Publication Date

  • April 25, 1997
  • Published In

    Keywords

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Cell Line
  • Dose-Response Relationship, Drug
  • Erythropoietin
  • Gene Expression
  • Genes, bcl-2
  • Genes, myc
  • Janus Kinase 2
  • Mice
  • Mitogens
  • Molecular Sequence Data
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-pim-1
  • Receptors, Erythropoietin
  • Recombinant Fusion Proteins
  • Sequence Deletion
  • Signal Transduction
  • Digital Object Identifier (doi)

    Pubmed Id

  • 9111017
  • Start Page

  • 11176
  • End Page

  • 11184
  • Volume

  • 272
  • Issue

  • 17