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

• Substitution of either F152 or K155 with alanine was found to specifically inhibit cytokine interaction with LIFR without affecting binding to CNTFR alpha or gp130 [30].
• Inducible expression and function of the leukemia inhibitory factor receptor was assessed by treatment with the histone deacetylase inhibitor depsipeptide [31].
• 2. We used chimeric receptors containing the intracellular domain of either the LIFR or gp130 to identify regions of the receptors required for induction of the m2 muscarinic acetylcholine receptor gene in IMR-32 and SN56 neuronal cells [32].
• The LIF receptor beta is expressed during the proliferative and secretory phases of the cycle and is restricted to the luminal epithelium [33].
• The changes in the tryptophan/CAA ratio from the end of term to the early puerperium were significantly and inversely related to serum IL-6, IL-IRA and LIF-R [34].

Physical interactions of LIFR

• 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 [22].
• Oncostatin M binds the high-affinity leukemia inhibitory factor receptor [35].
• In analogy to a recently published model of the IL-6R complex, a model of the active LIFR complex is suggested which positions the COOH-terminal CBM at LIF site I and the NH(2)-terminal CBM and the Ig-like domain at site III [36].

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

• GT1-7 cells were found to express CNTFR alpha, LIFR and gp130 genes, as shown by reverse transcription-polymerase chain reaction analysis, and the corresponding proteins, analysed by immunofluorescence and western blot [42].
• The expression of OMR beta and LIFR beta was determined by RT-PCR [43].
• Transcripts of the remaining two components of the CNTF receptor system, gp130 and LIFR beta, were found by Northern blotting in 83% and 70% of the tumors, respectively [44].
• In the present study we show that MDCK cells also express the LIF-R and respond to stimulation with human LIF by activation of tyrosine phosphorylation of signal transducer and activator of transcription-3 (STAT3), both however in an unpolarised fashion [45].
• OSM receptor and IL-6 receptor were also detectable by Western blotting whereas LIF receptor was only present as a faint band [46].

References