Cytoplasmic domains of the common beta-chain of the GM-CSF/IL-3/IL-5 receptors that are required for inducing differentiation or clonal suppression in myeloid leukaemic cell lines.
Granulocyte-macrophage colony stimulating factor (GM-CSF) is a cytokine that controls the production and function of myeloid cells by interaction with a cell surface receptor composed of a specific ligand-binding alpha-chain (hGMRalpha) and a shared signal-transducing beta-chain (beta c). Co-expression of human GMR alpha-chain and wild-type human beta c in two murine leukaemic cell lines (M1 and WEHI-3B D+) conferred the ability to terminally differentiate into macrophages when stimulated with human GM-CSF. Analysis of cytoplasmic truncation mutants of beta c showed that residues to amino acid 783 (numbering from the first amino acid of the leader sequence) were sufficient for the GM-CSF-dependent induction of all aspects of differentiation in both cell types. However, shorter truncations selectively lost, in a cell-specific manner, first the capacity to induce macrophage migration in agar and then cell surface differentiation antigens and clonal suppression of proliferative potential. The data suggest that different aspects of the differentiated phenotype can be dissociated with the required signalling pathways originating from distinct regions of the receptor cytoplasmic domain and cooperating to produce a fully differentiated macrophage. The cooperativity of these pathways and limiting cell signalling intermediate pool sizes could explain the observed cell line differences and may have implications for normal haemopoiesis.
Smith
A
A
Cooperative Research Centre for Cellular Growth Factors, PO Royal Melbourne Hospital, Victoria, Australia.
Metcalf
D
D
Nicola
N A
NA
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D002999:Clone Cells / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D007378:Interleukins / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
D007378:Interleukins; D011956:Receptors, Cell Surface; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor