JBC INTERFERin siRNA transfection reagent

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J Biol Chem, Vol. 274, Issue 9, 5415-5421, February 26, 1999

Oligomerization and Scaffolding Functions of the Erythropoietin Receptor Cytoplasmic Tail

Stephanie S. WatowichDagger , Kathleen D. Liu, Xiaoling XieDagger , Stephen Y. Lai, Aki Mikamiparallel , Gregory D. Longmoreparallel , and Mark A. Goldsmith

From the Dagger  Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, the  Gladstone Institute of Virology and Immunology, San Francisco, California 94141-9100 and the Department of Medicine, School of Medicine, University of California, San Francisco, California 94143, and the parallel  Departments of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110

Signal transduction by the erythropoietin receptor (EPOR) is activated by ligand-mediated receptor homodimerization. However, the relationship between extracellular and intracellular domain oligomerization remains poorly understood. To assess the requirements for dimerization of receptor cytoplasmic sequences for signaling, we overexpressed mutant EPORs in combination with wild-type (WT) EPOR to drive formation of heterodimeric (i.e. WT-mutant) receptor complexes. Dimerization of the membrane-proximal portion of the EPOR cytoplasmic region was found to be critical for the initiation of mitogenic signaling. However, dimerization of the entire EPOR cytoplasmic region was not required. To examine this process more closely, we generated chimeras between the intracellular and transmembrane portions of the EPOR and the extracellular domains of the interleukin-2 receptor beta  and gamma c chains. These chimeras allowed us to assess more precisely the signaling role of each receptor chain because only heterodimers of WT and mutant receptor chimeras form in the presence of interleukin-2. Coexpression studies demonstrated that a functional receptor complex requires the membrane-proximal region of each receptor subunit in the oligomer to permit activation of JAK2 but only one membrane-distal tail to activate STAT5 and to support cell proliferation. Thus, this study defines key relationships involved in the assembly and activation of the EPOR signal transduction complex which may be applicable to other homodimeric cytokine receptors.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.


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