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Gene Review

LIFR  -  leukemia inhibitory factor receptor alpha

Homo sapiens

Synonyms: CD118, LIF receptor, LIF-R, Leukemia inhibitory factor receptor, SJS2, ...
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Disease relevance of LIFR

  • Although all of 19 prolactinomas tested expressed gp130 and LIFR subunit mRNA and immunoreactive protein, only 3 of 19 prolactinomas expressed LIF mRNA [1].
  • Human choriocarcinoma cells expressing these mRNAs release soluble LIF-R [2].
  • By monovalently displaying human LIF on the surface of M13 phage and randomizing clusters of residues in regions predicted to be important for human LIFR binding, we have identified mutations, which lead to significant increases in affinity for binding to LIFR [3].
  • The recurrent translocation t(5;8)(p13;q12) in pleomorphic adenomas results in upregulation of PLAG1 gene expression under control of the LIFR promoter [4].
  • The growth promoting effects of CT-1 therefore indicate that signaling pathways emanating from gp130 and LIFR are coupled to cardiomyocyte hypertrophy [5].

Psychiatry related information on LIFR

  • No relationships between the mean normalized plasma GH levels (Z scores) and the sleep stages (wakefulness, sleep stages 1 and 2 ('light' sleep), slow-wave sleep (stages 3 and 4, SWS), and rapid eye movement (REM) sleep) were found in the patients or healthy subjects [6].
  • However, when the time of sampling of the plasma GH concentrations was lagged by 16 min with respect to the occurrence of the various sleep stages, significant correlations were found between plasma GH concentrations and SWS in both healthy subjects and patients [6].
  • Decreased SWS and MIC consumption in RYGB patients suggests that food-preference differences are partially responsible for the lower calorie intake and greater weight loss after RYGB than after HGP [7].
  • We conclude that in humans the primary host response induced by endotoxin initially suppresses REM sleep and increases stage 2 NREM sleep, but does not affect SWS [8].
  • Results show (a) significant conditioning effect was observed during slow wave sleep (SWS; stage 3 + 4) but not during stage 2; (b) some evidence was obtained to support the view that conditioning effect during sleep transferred to wakefulness [9].

High impact information on LIFR

  • The LIF receptor shares a common gp130 receptor subunit with the IL-6 cytokine superfamily [10].
  • Thus, the conversion of a bipartite LIF receptor into a tripartite CNTF receptor apparently occurs by the addition of the specificity-conferring element CNTFR alpha [11].
  • PCR amplification clearly revealed high levels of gp130 expression in AIDS-KS cells, while the transcript of LIF receptor alpha-subunit or IL-6 receptor alpha-subunit was not observed [12].
  • Thus, these results provide biological and biochemical evidence that Hck participates in signal transduction from the LIF receptor [13].
  • Consequently, the site on the hLIF molecule that confers species-specific binding to the hLIF-R and higher affinity binding to the mLIF-R, must constitute an additional interaction site to that used by both mLIF and hLIF to bind to the mLIF-R [14].

Chemical compound and disease context of LIFR

  • In young volunteers zopiclone exerts a beneficial effect on sleep continuity without suppression of SWS and REM sleep; psychomotor performance and vigilance seemed to be less impaired than under classical benzoediazepines [15].
  • During daytime recovery sleep after sleep deprivation, seganserin did not significantly enhance visually scored slow wave sleep (SWS, stages 3 + 4) or the EEG power density in the delta frequencies [16].
  • The cerebral glucose utilization during stage 2 SWS was lower than during wakefulness, but the variation did not significantly differ from zero (mean variation: -11.5 +/- 25.57%, P = 0.28) [17].
  • These findings correlate well with the effects of benzodiazepines on sleep stage 2 in humans and indicate that benzodiazepine hypnotics increase only the behaviorally lighter stage of SWS in rats as well as in human subjects [18].
  • As compared with placebo, trazodone induced an increase in sleep efficiency (primary target variable), TST, TSP and SWS (S3 + S4), as well as a decrease in wakefulness during the TSP, early morning awakening and S2 [19].

Biological context of LIFR

  • Using the full-length cytoplasmic domain and mutants with progressive C-terminal truncations or point mutations, we show that the two membrane-distal tyrosines with the YXXQ motif of LIFR are critical not only for STAT3 activation, but also for growth arrest and differentiation of WEHI-3B D+ cells [20].
  • Binding to LIFR occurs through a binding site characterized by an FXXK motif located at the N terminus of helix D (site III) [21].
  • Besides identifying a specific LIFR binding epitope on CNTF, our results suggest that receptor recognition sites of cytokines are organized as modules that are exchangeable even between cytokines with limited sequence homology [22].
  • In summary, LIFR and OSMR display differential effects on differentiation and phenotypic expression of osteogenic cells, most likely through different signal transduction pathways [23].
  • Mutation of Y115 of the cytoplasmic domain of LIFR eliminates receptor-mediated tyrosine phosphorylation of SHP-2 [24].

Anatomical context of LIFR

  • We also found that some myeloma cell lines (XG-4, XG-6, and XG-7) an fresh myeloma cells from 3 of 6 patients produced an autocrine IL-10 and that these cells constitutively expressed LIFR [25].
  • Our studies clearly demonstrate that the expression of two of the three CNTF receptor complex components, CNTFRalpha and LIFR, decreases during adipocyte differentiation [26].
  • Homodimers of the LIFR or OSMR cytoplasmic regions did not elicit responses in COS-7 cells but did in HepG2 cells and in MCF-7 breast carcinoma cells [27].
  • Moreover, our results indicate that the cross-talk among gp130 cytokines is mediated by the ability of these cytokines to induce ligand-dependent degradation of the LIFR, in a proteasome-independent manner, which coincides with decreased levels of LIFR at the plasma membrane [28].
  • We observed the expression of mRNA transcripts for OSM, OSM receptor subunit beta, leukaemia inhibitory factor receptor subunit (LIFR), and glycoprotein 130 in endometrial and endometriotic stromal cells [29].

Associations of LIFR with chemical compounds


Physical interactions of LIFR


Regulatory relationships of LIFR

  • A second region of hLIF that includes residues from the carboxyl terminus of the D-helix and A-B loop also had a weak influence on hLIF-R binding [37].
  • CNTF induced the tyrosine phosphorylation of LIFR and gp130, as well as of proteins with the molecular weights of 88/91 and 42 kDa [38].
  • Also, administration of pro-inflammatory cytokines such as IL-6 and IFN-alpha in humans acutely disturbed sleep while in rats such cytokines enhanced SWS and sleep [39].

Other interactions of LIFR

  • The D1 structural motif, located at the beginning of the D-helix of human CNTF, contains two amino acid residues, F152 and K155, which are conserved among all cytokines that signal through LIFR [30].
  • Thus, in spite of extensive functional similarities, differential signaling abilities of gp130, LIFR, and OSMR may become evident in a cell-type-specific manner [27].
  • Molecular modeling of the complex of LIF with the Ig-like domain of LIFR provides a clue for the superadditivity of the D214A/F284A double mutation [21].
  • Substitution of residues in the gp130 CBD, the LIFR CBD1, and the CNTFR BC domain that are expected to be involved in receptor-receptor interactions significantly reduced their interactions [40].
  • On cells that also express OSM receptor, OSM was not antagonized, demonstrating that the antagonist is specific for LIF-R [41].

Analytical, diagnostic and therapeutic context of LIFR


  1. Leukemia inhibitory factor regulates prolactin secretion in prolactinoma and lactotroph cells. Ben-Shlomo, A., Miklovsky, I., Ren, S.G., Yong, W.H., Heaney, A.P., Culler, M.D., Melmed, S. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  2. 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. Tomida, M. Leuk. Lymphoma (2000) [Pubmed]
  3. Affinity maturation of leukemia inhibitory factor and conversion to potent antagonists of signaling. Fairlie, W.D., Uboldi, A.D., McCoubrie, J.E., Wang, C.C., Lee, E.F., Yao, S., De Souza, D.P., Mifsud, S., Metcalf, D., Nicola, N.A., Norton, R.S., Baca, M. J. Biol. Chem. (2004) [Pubmed]
  4. The recurrent translocation t(5;8)(p13;q12) in pleomorphic adenomas results in upregulation of PLAG1 gene expression under control of the LIFR promoter. Voz, M.L., Aström, A.K., Kas, K., Mark, J., Stenman, G., Van de Ven, W.J. Oncogene (1998) [Pubmed]
  5. Cardiotrophin-1 and the role of gp130-dependent signaling pathways in cardiac growth and development. Wollert, K.C., Chien, K.R. J. Mol. Med. (1997) [Pubmed]
  6. Relationship of plasma growth hormone to slow-wave sleep in African sleeping sickness. Radomski, M.W., Buguet, A., Doua, F., Bogui, P., Tapie, P. Neuroendocrinology (1996) [Pubmed]
  7. Changes in eating behavior after horizontal gastroplasty and Roux-en-Y gastric bypass. Kenler, H.A., Brolin, R.E., Cody, R.P. Am. J. Clin. Nutr. (1990) [Pubmed]
  8. Endotoxin enhances EEG alpha and beta power in human sleep. Trachsel, L., Schreiber, W., Holsboer, F., Pollmächer, T. Sleep. (1994) [Pubmed]
  9. Classical conditioning during human NREM sleep and response transfer to wakefulness. Ikeda, K., Morotomi, T. Sleep. (1996) [Pubmed]
  10. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Auernhammer, C.J., Melmed, S. Endocr. Rev. (2000) [Pubmed]
  11. LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Davis, S., Aldrich, T.H., Stahl, N., Pan, L., Taga, T., Kishimoto, T., Ip, N.Y., Yancopoulos, G.D. Science (1993) [Pubmed]
  12. AIDS-associated Kaposi's sarcoma (KS) cells express oncostatin M (OM)-specific receptor but not leukemia inhibitory factor/OM receptor or interleukin-6 receptor. Complete block of OM-induced KS cell growth and OM binding by anti-gp130 antibodies. Murakami-Mori, K., Taga, T., Kishimoto, T., Nakamura, S. J. Clin. Invest. (1995) [Pubmed]
  13. Functional and biochemical association of Hck with the LIF/IL-6 receptor signal transducing subunit gp130 in embryonic stem cells. Ernst, M., Gearing, D.P., Dunn, A.R. EMBO J. (1994) [Pubmed]
  14. Inter-species chimeras of leukaemia inhibitory factor define a major human receptor-binding determinant. Owczarek, C.M., Layton, M.J., Metcalf, D., Lock, P., Willson, T.A., Gough, N.M., Nicola, N.A. EMBO J. (1993) [Pubmed]
  15. Effect of zopiclone and temazepam on sleep EEG parameters, psychomotor and memory functions in healthy elderly volunteers. Hemmeter, U., Müller, M., Bischof, R., Annen, B., Holsboer-Trachsler, E. Psychopharmacology (Berl.) (2000) [Pubmed]
  16. Effects of seganserin, a 5-HT2 antagonist, and temazepam on human sleep stages and EEG power spectra. Dijk, D.J., Beersma, D.G., Daan, S., van den Hoofdakker, R.H. Eur. J. Pharmacol. (1989) [Pubmed]
  17. Cerebral glucose utilization during stage 2 sleep in man. Maquet, P., Dive, D., Salmon, E., Sadzot, B., Franco, G., Poirrier, R., Franck, G. Brain Res. (1992) [Pubmed]
  18. Diazepam and midazolam increase light slow-wave sleep (SWS1) and decrease wakefulness in rats. Radulovacki, M., Sreckovic, G., Zak, R., Zahrebelski, G. Brain Res. (1984) [Pubmed]
  19. Insomnia in depression: differences in objective and subjective sleep and awakening quality to normal controls and acute effects of trazodone. Saletu-Zyhlarz, G.M., Abu-Bakr, M.H., Anderer, P., Gruber, G., Mandl, M., Strobl, R., Gollner, D., Prause, W., Saletu, B. Prog. Neuropsychopharmacol. Biol. Psychiatry (2002) [Pubmed]
  20. Cytoplasmic domains of the leukemia inhibitory factor receptor required for STAT3 activation, differentiation, and growth arrest of myeloid leukemic cells. Tomida, M., Heike, T., Yokota, T. Blood (1999) [Pubmed]
  21. Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor. Plun-Favreau, H., Perret, D., Diveu, C., Froger, J., Chevalier, S., Lelièvre, E., Gascan, H., Chabbert, M. J. Biol. Chem. (2003) [Pubmed]
  22. Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. Kallen, K.J., Grötzinger, J., Lelièvre, E., Vollmer, P., Aasland, D., Renné, C., Müllberg, J., Myer zum Büschenfelde, K.H., Gascan, H., Rose-John, S. J. Biol. Chem. (1999) [Pubmed]
  23. GP130/OSMR is the only LIF/IL-6 family receptor complex to promote osteoblast differentiation of calvaria progenitors. Malaval, L., Liu, F., Vernallis, A.B., Aubin, J.E. J. Cell. Physiol. (2005) [Pubmed]
  24. Differential regulation of leukemia inhibitory factor-stimulated neuronal gene expression by protein phosphatases SHP-1 and SHP-2 through mitogen-activated protein kinase-dependent and -independent pathways. Bartoe, J.L., Nathanson, N.M. J. Neurochem. (2000) [Pubmed]
  25. Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop. Gu, Z.J., Costes, V., Lu, Z.Y., Zhang, X.G., Pitard, V., Moreau, J.F., Bataille, R., Wijdenes, J., Rossi, J.F., Klein, B. Blood (1996) [Pubmed]
  26. The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. Zvonic, S., Cornelius, P., Stewart, W.C., Mynatt, R.L., Stephens, J.M. J. Biol. Chem. (2003) [Pubmed]
  27. Contributions of leukemia inhibitory factor receptor and oncostatin M receptor to signal transduction in heterodimeric complexes with glycoprotein 130. Hermanns, H.M., Radtke, S., Haan, C., Schmitz-Van de Leur, H., Tavernier, J., Heinrich, P.C., Behrmann, I. J. Immunol. (1999) [Pubmed]
  28. Cross-talk among gp130 cytokines in adipocytes. Zvonic, S., Baugh, J.E., Arbour-Reily, P., Mynatt, R.L., Stephens, J.M. J. Biol. Chem. (2005) [Pubmed]
  29. Menstrual cycle-specific inhibition of endometrial stromal cell proliferation by oncostatin M. Ohata, Y., Harada, T., Fujii, A., Yoshida, S., Iwabe, T., Terakawa, N. Mol. Hum. Reprod. (2001) [Pubmed]
  30. Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists. Di Marco, A., Gloaguen, I., Graziani, R., Paonessa, G., Saggio, I., Hudson, K.R., Laufer, R. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  31. Transformation of human bronchial epithelial cells alters responsiveness to inflammatory cytokines. Loewen, G.M., Tracy, E., Blanchard, F., Tan, D., Yu, J., Raza, S., Matsui, S., Baumann, H. BMC Cancer (2005) [Pubmed]
  32. Tyrosines 905 and 915 of gp130 are required for maximum induction of m2 muscarinic acetylcholine receptor and VIP gene transcription by cytokines in neuronal cells. Rosoff, M.L., Nathanson, N.M. Cell. Mol. Neurobiol. (1999) [Pubmed]
  33. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Cullinan, E.B., Abbondanzo, S.J., Anderson, P.S., Pollard, J.W., Lessey, B.A., Stewart, C.L. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  34. Effects of pregnancy and delivery on the availability of plasma tryptophan to the brain: relationships to delivery-induced immune activation and early post-partum anxiety and depression. Maes, M., Ombelet, W., Verkerk, R., Bosmans, E., Scharpé, S. Psychological medicine. (2001) [Pubmed]
  35. Oncostatin M binds the high-affinity leukemia inhibitory factor receptor. Gearing, D.P., Bruce, A.G. New Biol. (1992) [Pubmed]
  36. The upper cytokine-binding module and the Ig-like domain of the leukaemia inhibitory factor (LIF) receptor are sufficient for a functional LIF receptor complex. Aasland, D., Oppmann, B., Grötzinger, J., Rose-John, S., Kallen, K.J. J. Mol. Biol. (2002) [Pubmed]
  37. Characterization of the receptor binding sites of human leukemia inhibitory factor and creation of antagonists. Hudson, K.R., Vernallis, A.B., Heath, J.K. J. Biol. Chem. (1996) [Pubmed]
  38. Characterization of receptors for ciliary neurotrophic factor on rat hippocampal astrocytes. Alderson, R.F., Pearsall, D., Lindsay, R.M., Wong, V. Brain Res. (1999) [Pubmed]
  39. Brain-immune interactions in sleep. Marshall, L., Born, J. Int. Rev. Neurobiol. (2002) [Pubmed]
  40. Solution structure of the C-terminal domain of the ciliary neurotrophic factor (CNTF) receptor and ligand free associations among components of the CNTF receptor complex. Man, D., He, W., Sze, K.H., Gong, K., Smith, D.K., Zhu, G., Ip, N.Y. J. Biol. Chem. (2003) [Pubmed]
  41. An antagonist for the leukemia inhibitory factor receptor inhibits leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M. Vernallis, A.B., Hudson, K.R., Heath, J.K. J. Biol. Chem. (1997) [Pubmed]
  42. Expression of functional ciliary neurotrophic factor receptors in immortalized gonadotrophin-releasing hormone-secreting neurones. Dozio, E., Watanobe, H., Ruscica, M., Maggi, R., Motta, M., Magni, P. J. Neuroendocrinol. (2005) [Pubmed]
  43. Oncostatin M (OM) promotes the growth of DU 145 human prostate cancer cells, but not PC-3 or LNCaP, through the signaling of the OM specific receptor. Mori, S., Murakami-Mori, K., Bonavida, B. Anticancer Res. (1999) [Pubmed]
  44. CNTF and its receptor subunits in human gliomas. Weis, J., Schönrock, L.M., Züchner, S.L., Lie, D.C., Sure, U., Schul, C., Stögbauer, F., Ringelstein, E.B., Halfter, H. J. Neurooncol. (1999) [Pubmed]
  45. Polarity and lipid raft association of the components of the ciliary neurotrophic factor receptor complex in Madin-Darby canine kidney cells. Buk, D.M., Waibel, M., Braig, C., Martens, A.S., Heinrich, P.C., Graeve, L. J. Cell. Sci. (2004) [Pubmed]
  46. Glycoprotein 130 ligand oncostatin-M induces expression of vascular endothelial growth factor in human adult cardiac myocytes. Weiss, T.W., Speidl, W.S., Kaun, C., Rega, G., Springer, C., Macfelda, K., Losert, U.M., Grant, S.L., Marro, M.L., Rhodes, A.D., Fuernkranz, A., Bialy, J., Ullrich, R., Holzmann, P., Pacher, R., Maurer, G., Huber, K., Wojta, J. Cardiovasc. Res. (2003) [Pubmed]
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