The box-1 region of the leukemia inhibitory factor receptor alpha-chain cytoplasmic domain is sufficient for hemopoietic cell proliferation and differentiation.
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that acts on a variety of cell types and regulates cell proliferation and differentiation. The functional receptor for LIF is composed of LIFR alpha-chain (LIFRalpha) and gp130 both of which are shared in the functional receptors for oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1. By using stable transfection of wild-type or cytoplasmic deletion mutants of LIFRalpha together with full-length gp130 into Ba/F3 cells, we found that cells expressing gp130 and an extensively deleted mutant LIFRalpha containing only the box-1 region were capable of proliferating in response to LIF, although LIF-dependent long term growth of these cells was seriously impaired. Using a similar strategy to generate WEHI-3BD+ cells expressing gp130 and wild-type or truncation mutants of LIFRalpha, studies revealed that the box-1 region of the LIFRalpha was also sufficient for LIF-dependent induction of different aspects of differentiation, including up-regulation of macrophage surface marker expression, morphological change, and cell migration in agar culture. However, the C-terminal region of the LIFRalpha, although not essential for intracellular signaling, was important for efficient receptor-mediated ligand internalization. In summary, the membrane-proximal box-1 region plays a dominant role in LIF-induced signal transduction of both proliferation and differentiation.
Zhang
Y
Y
Walter and Eliza Hall Institute for Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Victoria 3050, Australia.
Willson
T
T
Metcalf
D
D
Cary
D
D
Hilton
D J
DJ
Clark
R
R
Nicola
N A
NA
D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000494:pharmacology* / Q000502:physiology; D046911:Macromolecular Substances; D018121:Receptors, Cytokine / Q000737:chemistry / Q000502:physiology*; D053606:Receptors, OSM-LIF; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017384:Sequence Deletion; D013936:Thymidine / Q000378:metabolism; D014162:Transfection
D006131:Growth Inhibitors; D007377:Interleukin-3; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D046911:Macromolecular Substances; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D013936:Thymidine