Stuve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality. Clinical overlap with Schwartz-Jampel type 2 syndrome (SJS2) has suggested that SWS and SJS2 could be allelic disorders. Through studying a series of 19 families with SWS/SJS2, we have mapped the disease gene to chromosome 5p13.1 at locus D5S418 (Zmax=10.66 at theta =0) and have identified null mutations in the leukemia inhibitory factor receptor (LIFR or gp190 chain) gene. A total of 14 distinct mutations were identified in the 19 families. An identical frameshift insertion (653_654insT) was identified in families from the United Arab Emirates, suggesting a founder effect in that region. It is interesting that 12/14 mutations predicted premature termination of translation. Functional studies indicated that these mutations alter the stability of LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells. We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13.
We report the existence of eight different interleukin-15 receptor ␣-chain (IL-15R␣) transcripts resulting from exon-splicing mechanisms within the IL-15R␣ gene. Two main classes of transcripts can be distinguished that do or do not (⌬2 isoforms) contain the exon 2-coding sequence. Both classes were expressed in numerous cell lines and tissues (including peripheral blood lymphocytes) at comparable levels and could be transcribed in COS-7 cells, and the proteins were expressed at the cell surface. Both receptor forms displayed numerous glycosylation states, reflecting differential usage of a single N-glycosylation site as well as extensive O-glycosylations. Whereas IL-15R␣ bound IL-15 with high affinity, ⌬2IL-15R␣ was unable to bind IL-15, thus revealing the indispensable role of the exon 2-encoded domain in cytokine binding. A large proportion of IL-15R␣ was expressed at the nuclear membrane with some intranuclear localization, supporting a potential direct action of the IL-15⅐IL-15R␣ complex at the nuclear level. In sharp contrast, ⌬2IL-15R␣ was found only in the non-nuclear membrane compartments, indicating that the exon 2-encoded domain (which is shown to contain a potential nuclear localization signal) plays an important role in receptor post-translational routing. Together, our data indicate that exon 2 splicing of human IL-15R␣ is a natural process that might play regulatory roles at different levels.
The cytokine receptor subunits gp130, leukemia inhibitory factor receptor ␣ (LIFR␣), and oncostatin M receptor  (OSMR) transduce OSM signals that regulate gene expression and cell proliferation. After ligand binding and activation of the Janus protein-tyrosine kinase/STAT and mitogen-activated protein kinase signal transduction pathways, negative feedback processes are recruited. These processes attenuate receptor action by suppression of cytokine signaling and by downregulation of receptor protein expression. This study demonstrates that in human fibroblasts or epithelial cells, OSM first decreases the level of gp130, LIFR␣, and OSMR by ligand-induced receptor degradation and then increases the level of the receptors by enhanced synthesis. The transcriptional induction of gp130 gene by OSM involves STAT3. Various cell lines expressing receptor subunits to the different interleukin-6 class cytokines revealed that only LIFR␣ degradation is promoted by activated ERK and that degradation of gp130, OSMR, and a fraction of LIFR␣ involves mechanisms that are separate from signal transduction. These mechanisms include ligand-mediated dimerization, internalization, and endosomal/lysosomal degradation. Proteosomal degradation appears to involve a fraction of receptor subunit proteins that are ubiquitinated independently of ligand binding.Interleukin-6 (IL-6), 1 oncostatin M (OSM), and leukemia inhibitory factor (LIF) are functionally and structurally related and are part of the IL-6 family of cytokines (1-5). Each IL-6 cytokine is recognized by a specific ligand binding receptor subunit. In humans, OSM is exceptional in that it interacts with gp130 and with either LIFR␣ or OSMR to form the high affinity, signaling-competent OSM receptor complex I or II (3, 4). Ligand-induced oligomerization of receptor subunits activates Janus protein-tyrosine kinases (JAKs), which in turn phosphorylate tyrosine residues in the receptor cytoplasmic domain. These phosphorylated tyrosines create docking sites for STAT transcription factors (STAT1, -3, and -5), proteintyrosine phosphatase SHP-2, and linker proteins such as Gab-1, Grb2, or SHC, which propagate the signal to other pathways (ERK 1/2, JNK, phosphatidylinositol 3-kinase; Refs. 1-8). Receptor signaling is manifested by the activation of genes such as acute phase proteins (2) or the cyclin-dependent kinase inhibitor p21 WAF1 , which is primarily activated through STATs (9) and immediate early response genes such as c-fos, c-jun, and egr-1 primarily through ERK 1/2 (6).Signaling by IL-6 cytokine receptors is transient, often restricted temporally and in magnitude by the action of negative regulators. The SH2 domain-containing protein-tyrosine phosphatases SHP1 and -2, through their catalytic function, attenuate the activity of receptor-associated JAKs and consequently lower the induction of STAT-dependent genes (4, 6). The suppressor of cytokine signaling SOCS1 and -3 are rapidly induced by IL-6 cytokines and, through their SH2 domain, interact and deactivate JAKs or gp130 (4,...
Leukemia inhibitory factor (LIF) signals via the heterodimeric receptor complex comprising the LIF receptor ␣ subunit (LIFR␣) and the common signal transducing subunit for interleukin-6 cytokine receptors, gp130. This study demonstrates that in different cell types, the level of LIFR␣ decreases during treatment with LIF or the closely related cytokine oncostatin M (OSM). Moreover, insulin and epidermal growth factor induce a similar LIFR␣ down-regulation. The regulated loss of LIFR␣ is specific since neither gp130 nor OSM receptor  shows a comparable change in turnover. LIFR␣ downregulation correlates with reduced cell responsiveness to LIF. Using protein kinase inhibitors and point mutations in LIFR␣, we demonstrate that LIFR␣ downregulation depends on activation of extracellular signalregulated kinase 1/2 and phosphorylation of the cytoplasmic domain of LIFR␣ at serine 185. This modification appears to promote the endosomal/lysosomal pathway of the LIFR␣. These results suggest that extracellular signal-regulated kinase-activating factors like OSM and growth factors have the potential to lower specifically LIF responsiveness in vivo by regulating LIFR␣ half-life. Leukemia inhibitory factor (LIF)1 is one member of the interleukin (IL)-6-type family of cytokines that also include IL-6, IL-11, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and neurotrophin-1. LIF is a pleiotropic cytokine that, among other functions, induces differentiation of mouse monocytic leukemia M1 cells, conversion of sympathetic neurons from the adrenergic to cholinergic phenotype, suppresses the differentiation of embryonic stem cells, enhances proliferation of myoblasts, and facilitates endometrial implantation of embryos (reviewed in Refs. 1 and 2).LIF also plays a role in the systemic inflammatory response, activating the hypothalamic-adrenal axis, and inducing the acute phase reaction of the liver (3). In hepatocytes, LIF, similar to other IL-6 cytokines, stimulates the enhanced expression of a set of plasma proteins, termed acute phase proteins (APP) (4). The precise pattern of APP expression is determined by the action of IL-6 cytokines in combination with various other inflammatory mediators, endocrine hormones, and growth factors (5). For instance, during the acute phase reaction, insulin is increased 3-fold (6) and then modulates the cytokine regulation of APP genes (7,8). In myoblasts, IGF-1 also reduces LIF action, apparently by down-regulating LIF receptor number (9).LIFR␣ is a 190-kDa transmembrane protein with low affinity for LIF. In combination with gp130 subunit, it forms the high affinity LIF receptor complex (10, 11). As described in the human system, OSM also uses LIFR␣ and gp130 subunits to form a high affinity OSM receptor complex (then termed OSMR complex type I). CNTF, CT-1, and neurotrophin-1 also utilize LIFR␣ and gp130 subunits (reviewed in Refs. 12 and 13). In addition to the shared LIFR␣/gp130 complex used by either LIF or OSM, a specific OSM receptor complex (type II) has bee...
The related members of the interleukin-6 (IL-6) family of cytokines, leukemia inhibitory factor (LIF), oncostatin M (OSM) and IL-6 are inflammatory mediators that control differentiated cell functions as well as proliferation. The cellular responsiveness to these cytokines is largely determined by the expression of the appropriate receptor proteins. The receptor expression profile for each cell type is established during differentiation and is often altered during oncogenic transformation. Since inhibition of histone deacetylases (HDAC) has the potential to re-activate epigenetically silenced genes, we asked whether inhibition of HDAC enhances the expression of IL-6 cytokine receptors and, thus, increase desirable cytokine responses. We demonstrate that treatment with FR901228 (FR), an HDAC inhibitor, increases the responsiveness to LIF in different cell types, including normal fibroblasts, epithelial cells, macrophages and splenocytes, as well as various tumor cell lines. Depending on the cell type, FR treatment also enhances the responsiveness to OSM and IL-6. These effects involve a transcriptional induction of the cytokine receptor subunits LIFRa, OSMRb, gp130, or the transcription factor STAT3. FR-specific induction of LIFRa occurs independently of de novo protein synthesis and cell proliferation and is mediated in part by the CBP/p300 coactivator. Chromatin immunoprecipitation experiments indicate that the expression of LIFRa and gp130 genes correlates with the level of acetylated histone 3 associated with the receptor promoter regions. The FR-stimulated expression of IL-6-type cytokine receptors in certain tumor cells also provided improved conditions for suppression of cell growth by taking advantage of the growth inhibitory effect of these cytokines.
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