An antagonist for the leukemia inhibitory factor receptor inhibits leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M.
The leukemia inhibitory factor receptor (LIF-R) is activated not only by LIF, but also by cardiotrophin-1, ciliary neurotrophic factor with its receptor, and oncostatin M (OSM). Each of these cytokines induces the hetero-oligomerization of LIF-R with gp130, a signal-transducing subunit shared with interleukin-6 and interleukin-11. The introduction of mutations into human LIF that reduced the affinity for gp130 while retaining affinity for LIF-R has generated antagonists for LIF. In the current study, a LIF antagonist that was free of detectable agonistic activity was tested for antagonism against the family of LIF-R ligands. On cells that express LIF-R and gp130, all LIF-R ligands were antagonized. On cells that also express OSM receptor, OSM was not antagonized, demonstrating that the antagonist is specific for LIF-R. Ligand-triggered tyrosine phosphorylation of both LIF-R and gp130 was blocked by the antagonist. The antagonist is therefore likely to work by preventing receptor oligomerization.
Vernallis
A B
AB
CRC Growth Factor Group, School of Biochemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Hudson
K R
KR
Heath
J K
JK
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D020934:Ciliary Neurotrophic Factor; D003001:Cloning, Molecular; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004926:Escherichia coli; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053683:Oncostatin M; D010455:Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000502:physiology*; D053606:Receptors, OSM-LIF; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C508351:OSM protein, human; D010455:Peptides; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D011994:Recombinant Proteins; D053683:Oncostatin M; C092073:cardiotrophin 1