Erythropoietin (EPO) regulates the proliferation and differentiation of erythroid cells through interaction with its receptor (EPOR). Although EPOR is a member of the cytokine receptor superfamily and lacks a kinase domain, EPO induces tyrosine phosphorylation, which is correlated with gene transcription and mitogenesis. Here we demonstrate that EPO induces tyrosine phosphorylation of JAK2 kinase and activates its in vitro autophosphorylation. Using EPOR mutants, phosphorylation and activation of kinase activity correlate with the induction of mitogenesis. Furthermore, JAK2 physically associates with a membrane-proximal region of the EPOR cytoplasmic domain that is required for biological activity. The results support the hypothesis that JAK2 is the kinase that couples EPO binding to tyrosine phosphorylation and mitogenesis.
Bibliographical noteFunding Information:
This work was supported in part by the National Cancer Institute Cancer Center Support grant P30 CA21765 by grant ROl DK42932 from the National Institute of Diabetes and Digestive and Kidney Diseases, and by the American Lebanese Syrian Associated Charities. We would like to thank Linda Snyder and Cynthia Miller for excellent technical assistance in these studies.
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