Inhibition of granulocyte-macrophage colony-stimulating factor receptor function by a splice variant of the common beta-receptor subunit.
The receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are composed of a ligand-specific alpha-chain (eg, alpha-GM-CSF receptor [alpha-GMR]) and a common beta-subunit (beta-GMR). Ligand binding is believed to induce assembly or conformational changes in preformed complexes containing more than one alpha- and beta-subunit in the activated receptor complex. To analyze the function of a splice variant of beta-GMR with a truncation in the intracellular domain (beta-GMR(IT)), BaF-3 cells expressing human alpha-GMR plus beta-GMR were transfected with beta-GMR(IT). In these cells, coexpression of beta-GMR(IT) inhibits GM-CSF-mediated survival and proliferation in a GM-CSF concentration-dependent manner. To analyze the effect of cytoplasmic assembly of truncated and full-length intracellular beta-GMR sequences, beta-GMR and beta-GMR(IT) were coexpressed with different chimeric alpha/beta-GMR constructs. Whereas both beta-GMR and beta-GMR(IT) generate high-affinity GMR complexes in the presence of alpha/beta-GMR, beta-GMR(IT) inhibits while beta-GMR supports proliferation and cell survival mediated by alpha/beta-GMR. Correspondingly, beta-GMR, but not beta-GMR(IT), generates functional GMR complexes when coexpressed with a defective alpha/beta-GMR construct. These data indicate that beta-GMR(IT) can inhibit survival and mitogenic signaling of the wild-type GMR and demonstrate that recruitment of alternatively spliced receptor subunits may regulate the function of heteromeric cytokine receptors.
Wagner
K
K
Department of Hematology and Oncology, Hannover Medical School, and the Center for Cell Therapy/Cytonet, Hannover, Germany.
Kafert-Kasting
S
S
Heil
G
G
Ganser
A
A
Eder
M
M
D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016368:Frameshift Mutation; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D051379:Mice; D021122:Protein Subunits; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D021122:Protein Subunits; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor