Reassessment of interactions between hematopoietic receptors using common beta-chain and interleukin-3-specific receptor beta-chain-null cells: no evidence of functional interactions with receptors for erythropoietin, granulocyte colony-stimulating factor, or stem cell factor.
Mice lacking both the gene encoding the shared receptor for granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 common beta-chain (B(c)) and the gene for the IL-3 specific receptor (BIL3) were generated. This was achieved by targeting the B(c) locus in embryonic stem cells that were heterozygous for a null mutation of BIL3. Cells from mice generated with the doubly targeted embryonic stem cells were unresponsive to all 3 cytokines. Considerable previous data suggested a role for common beta-chain (beta(c)) in modulating signaling of cytokines including erythropoietin (EPO), G-CSF, and stem cell factor (SCF). However, bone marrow cells from mice lacking beta(c) and beta(IL3) showed normal responsiveness to these cytokines. Thus, there was no evidence for a biologically significant interaction between signaling via beta(c) or beta(IL3) and signaling by EPO, G-CSF, or SCF. Previously documented biochemical phenomena, including receptor transmodulation, receptor transphosphorylation, and even direct physical interaction, involving the beta(c)/beta IL-3 receptor systems do not reflect genuine interactions of physiological significance in primary hematopoietic cells. This study provided results that challenge conclusions previously established using a variety of biochemical assays. (Blood. 2000;96:1588-1590)
Scott
C L
CL
The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria, Australia. scottc@wehi.edu.au
Robb
L
L
Papaevangeliou
B
B
Mansfield
R
R
Nicola
N A
NA
Begley
C G
CG
D000818:Animals; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D020239:Receptor Cross-Talk; D017467:Receptors, Erythropoietin / Q000235:genetics* / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics*; D019089:Stem Cell Factor / Q000378:metabolism
D007377:Interleukin-3; D017467:Receptors, Erythropoietin; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016185:Receptors, Interleukin-3; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit