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Maturation of Erythroid Cells and Erythroleukemia Development Are Affected by the Kinase Activity of Lyn¹

Laboratory for Cancer Medicine, Western Australian Institute for Medical Research, Royal Perth Hospital and Department of Biochemistry, The University of Western Australia, Perth WA 6000, Australia [P. A. T., G. A. P., D. J. M., M. J. W., M. K. S., V. C., J. H. W., E. I., S. P. K.]; Institute of Medical Biochemistry, University of Rostock, Rostock, Germany [T. B.]; Basic Research Laboratory, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201 [D. L.]; Institute of Medical Immunology, Charite, Humboldt-University, Berlin, Germany [J. S-M.]; and Terry Fox Laboratory, BC Cancer Agency, Vancouver V5Z1L3, Canada [G. K.]

This study examined the impact of the tyrosine kinase Lyn on erythropoietin-induced intracellular signaling in erythroid cells. In J2E erythroleukemic cells, Lyn coimmunoprecipitated with numerous proteins, including SHP-1, SHP-2, ras-GTPase-activating protein, signal transducers and activators of transcription (STAT) 5a, STAT5b, and mitogen-activated protein kinase; however, introduction of a dominant-negative Lyn (Y397F Lyn) inhibited the interaction of Lyn with all of these molecules except SHP-1. Cells containing the dominant-negative Lyn displayed altered intracellular phosphorylation patterns, including mitogen-activated protein kinase, but not erythropoietin receptor, Janus-activated kinase (JAK) 2, or STAT5. As a consequence, erythropoietin-initiated differentiation and basal proliferation were severely impaired. Y397F Lyn reduced the protein levels of erythroid transcription factors erythroid Kruppel-like factor and GATA-1 up to 90%, which accounts for the inability of J2E cells expressing Y397F Lyn to synthesize hemoglobin. Although Lyn was shown to bind several sites on the cytoplasmic domain of the erythropoietin receptor, it was not activated when a receptor mutated at the JAK2 binding site was ectopically expressed in J2E cells, indicating that JAK2 is the primary kinase in erythropoietin signaling and that Lyn is a secondary kinase. In normal erythroid progenitors, erythropoietin enhanced phosphorylation of Lyn; moreover, exogenous Lyn increased colony forming unit-erythroid, but not burst forming unit-erythroid, colonies from normal progenitors, demonstrating a stage-specific effect of the kinase. Significantly, altering Lyn activity in J2E cells had a profound effect on the development of erythroleukemias in vivo: the mortality rate was markedly reduced and latent period extended when either wild-type Lyn or Y397F Lyn was introduced into these cells. Taken together, these data show that Lyn plays an important role in intracellular signaling in nontransformed and leukemic erythroid cells.

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