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Blood, 1 January 2002, Vol. 99, No. 1, pp. 102-110
HEMATOPOIESIS
Identification of the human erythropoietin receptor region
required for Stat1 and Stat3 activation
Keita Kirito,
Koichi Nakajima,
Tomoko Watanabe,
Mie Uchida,
Masaru Tanaka,
Keiya Ozawa, and
Norio Komatsu
From the Division of Hematology, Department of
Medicine, Jichi Medical School, Tochigi, Japan; and the Department of
Molecular Oncology, Biomedical Research Center, Osaka University
Medical School, Japan.
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.
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