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(Journal of Leukocyte Biology. 2002;72:1246-1255.)
© 2002 by Society for Leukocyte Biology

Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the ß-subunit of the GM-CSF receptor

Hanson Institute, Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, and Department of Medicine, Adelaide University, South Australia

Correspondence: Thomas J. Gonda, Bionomics Ltd., 31 Dalgleish Street, Thebarton, South Australia 5031. E-mail: tgonda{at}bionomics.com.au

Several reports have suggested an interaction between the erythropoietin receptor (EpoR) and the shared signaling subunit (hß_c) of the human granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 receptors, although the functional consequences of this interaction are unclear. We previously showed that in vivo expression of constitutively active extracellular (EC) mutants of hß_c induces erythrocytosis and Epo independence of erythroid colony-forming units (CFU-E). This occurs despite an apparent requirement of these mutants for the GM-CSF receptor -subunit (GMR), which is not expressed in CFU-E. Here, we show that coexpression of hß_c EC mutants and EpoR in BaF-B03 cells, which lack GMR, results in factor-independent proliferation and JAK2 activation. Mutant receptors that cannot activate JAK2 fail to produce a functional interaction. As there is no detectable phosphorylation of hß_c on intracellular tyrosine residues, EpoR displays constitutive tyrosine phosphorylation. These observations suggest that JAK2 activation mediates cross-talk between EC mutants of hß_c and EpoR. The implications of these data are discussed as are our findings that activated hß_c mutants can functionally interact with certain other cytokine receptors.

Key Words: erythropoietin receptor • factor independence • JAK2 • tyrosine phosphorylation

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