Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation.
Signal transducers and activators of transcription (Stat) proteins play important roles in the regulation of hematopoiesis as downstream molecules of cytokine signal transduction. It was previously demonstrated that erythropoietin (EPO), a major regulator of erythropoiesis, activates 3 different Stat members, Stat1, Stat3, and Stat5, in a human EPO-dependent cell line, UT-7/EPO. To clarify the mechanism by which EPO activates Stat1 and Stat3 via the EPO receptor (EPOR), a series of chimeric receptors was constructed bearing the extracellular domain of the granulocyte colony-stimulating factor receptor linked to the transmembrane domain of EPOR and the full length or several mutants of the cytoplasmic domain of EPOR, and these chimeric receptor complementary DNAs were introduced into UT-7/EPO cells. Tyr432 on human EPOR was important for activation of Stat1 and Stat3 and c-myc gene induction. In addition, Jak2 and Fes tyrosine kinases were involved in EPO-induced activation of Stat1 and Stat3. These results indicate that Stat1 and Stat3 are activated by EPO via distinct mechanisms from Stat5.
Kirito
Keita
K
Division of Hematology, Department of Medicine, Jichi Medical School, Tochigi, Japan.
Nakajima
Koichi
K
Watanabe
Tomoko
T
Uchida
Mie
M
Tanaka
Masaru
M
Ozawa
Keiya
K
Komatsu
Norio
N
D002455:Cell Division; D004268:DNA-Binding Proteins / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004920:Erythropoiesis; D004921:Erythropoietin / Q000494:pharmacology; D015681:Fusion Proteins, gag-onc / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2; D007938:Leukemia; D016297:Mutagenesis, Site-Directed; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine
D004268:DNA-Binding Proteins; D015681:Fusion Proteins, gag-onc; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D017467:Receptors, Erythropoietin; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C068415:v-fps oncogene protein, Fujinami sarcoma virus