Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the beta-subunit of the GM-CSF receptor.
Several reports have suggested an interaction between the erythropoietin receptor (EpoR) and the shared signaling subunit (hbeta(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 hbeta(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 alpha-subunit (GMRalpha), which is not expressed in CFU-E. Here, we show that coexpression of hbeta(c) EC mutants and EpoR in BaF-B03 cells, which lack GMRalpha, 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 hbeta(c) on intracellular tyrosine residues, EpoR displays constitutive tyrosine phosphorylation. These observations suggest that JAK2 activation mediates cross-talk between EC mutants of hbeta(c) and EpoR. The implications of these data are discussed as are our findings that activated hbeta(c) mutants can functionally interact with certain other cytokine receptors.
Blake
Timothy J
TJ
Hanson Institute, Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, South Australia.
Jenkins
Brendan J
BJ
D'Andrea
Richard J
RJ
Gonda
Thomas J
TJ
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D006801:Humans; D053614:Janus Kinase 2; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins; D020239:Receptor Cross-Talk / Q000502:physiology; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D017467:Receptors, Erythropoietin; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2