Structural and functional studies on the leukemia inhibitory factor receptor (LIF-R): gene and soluble form of LIF-R, and cytoplasmic domain of LIF-R required for differentiation and growth arrest of myeloid leukemic cells.
The leukemia inhibitory factor receptor (LIF-R) subunit is a component of cell-surface receptor complexes for the multifunctional cytokines, LIF, cardiotrophin-1, ciliary neurotrophic factor, and human oncostatin M. The structure of the human LIF-R gene is similar to that of the mouse gene. The transmembrane receptor is encoded by 19 exons. Two distinct 5' non-coding exons are present, indicating the existence of alternative promoters. An extra-exon specific to the mouse soluble receptor contains a stop codon and polyadenylation signals in a B2 repetitive element. On the other hand, LIF-R mRNAs containing unspliced introns are abundantly present in human tissues. These intronic sequences introduce a termination codon before the transmembrane domain. Human choriocarcinoma cells expressing these mRNAs release soluble LIF-R. The cytoplasmic domain of LIF-R can generate the signals for growth arrest and differentiation of mouse myeloid leukemic cells when they are induced to form a homodimer of the cytoplasmic domain independently of gp130. Two membrane-distal tyrosines on the YXXQ motif of LIF-R are critical not only for STAT3 activation but also for growth arrest and macrophage differentiation of WEHI-3B D+ cells.
Tomida
M
M
Laboratory of Carcinogenesis and Cancer Prevention, Saitama Cancer Center Research Institute, 818 Komuro, Ina, Saitama 362-0806, Japan. tomida@cancer-c.pref.saitama.jp
D020816:Amino Acid Motifs; D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000502:physiology; D019281:Dimerization; D054278:Embryonal Carcinoma Stem Cells; D005260:Female; D005786:Gene Expression Regulation; D005796:Genes; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D007951:Leukemia, Myeloid / Q000473:pathology; D008222:Lymphokines / Q000502:physiology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D018121:Receptors, Cytokine / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; D012689:Sequence Homology, Nucleic Acid; D012995:Solubility; D013045:Species Specificity; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000502:physiology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; 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; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008222:Lymphokines; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators