Mitogenic signaling and inhibition of apoptosis via the erythropoietin receptor Box-1 domain.
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.
Joneja
B
B
Graduate Program in Biochemistry and Molecular Biology, Center for Gene Regulation and the Department of Veterinary Science, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Wojchowski
D M
DM
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology*; D015870:Gene Expression; D019254:Genes, bcl-2; D016259:Genes, myc; D053614:Janus Kinase 2; D051379:Mice; D008934:Mitogens / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D017384:Sequence Deletion; D015398:Signal Transduction
D008934:Mitogens; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1