Internalization of the interleukin 6 signal transducer gp130 does not require activation of the Jak/STAT pathway

Thiel, Stefan; Behrmann, Iris; Dittrich, Elke; Muys, Leon; Tavernier, Jan; Wijdenes, John; Heinrich, Constanze; Graeve, Lutz

doi:10.1042/bj3300047

Cited by 61 publications

(48 citation statements)

References 41 publications

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“…These results suggest that the dileucine motif is required for IL-13-IL-13R␣2 chain complex internalization. Thus, our results confirm previous observations that the dileucine motif is necessary for internalization of various cytokine-receptor complexes (22)(23)(24)(25)(26)(27)(28)(29)(30).…”

Section: Discussionsupporting

confidence: 82%

“…It has been demonstrated that a dileucine motif in the intracellular domain of various receptor systems (e.g. interleukin-6 receptor (IL-6R) gp130, granulocyte colony-stimulating factor receptor, epidermal growth factor receptor, growth hormone receptor, human insulin receptor, ␤ 2 -adrenergic receptor, lutropin/choriogonadotropin receptor, and erythropoietin receptor) plays an essential role in the internalization of ligand (22)(23)(24)(25)(26)(27)(28)(29)(30).…”

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confidence: 99%

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Identification of Distinct Roles for a Dileucine and a Tyrosine Internalization Motif in the Interleukin (IL)-13 Binding Component IL-13 Receptor α2 Chain

Kawakami

Takeshita

Puri

2001

Journal of Biological Chemistry

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Interleukin (IL)-13 receptor ␣2 (IL-13R␣2Unlike receptors for the related cytokine IL-4, 1 the receptors for IL-13 (IL-13R) have not been well characterized. We have been studying the structure of IL-13R in various cell types (1-6). We reported that IL-13 binds to two isoforms of 65-kDa proteins in human renal cell carcinoma cells, and one of these proteins also binds IL-4 (1). On the basis of binding characteristics, cross-linking, and displacement of radiolabeled IL-4 and IL-13 in various cell types, we hypothesized that, similar to the IL-4R system, IL-13R may also exist as three different types (1-6). Two different chains of the IL-13 receptor, IL-13R␣1 and IL-13R␣2 (also known as IL-13R␣Ј and IL-13R␣, respectively), have been cloned and correspond to the two 65-kDa isoforms as we originally proposed (1). The murine and human IL-13R␣1 chains were cloned first (7,8). This chain binds IL-13 at low levels, but when coupled with the IL-4R␣ chain (also known as IL-4R␤) it binds IL-13 with higher affinity and mediates IL-13-induced signaling (9, 10). The second chain of IL-13R, termed IL-13R␣2, has been cloned from a human renal cell carcinoma cell line (Caki-1). This chain has 50% identity to the IL-5R at the DNA level, has a short intracellular domain, and binds IL-13 with high affinity (11).Cells selectively internalize specific surface ligand-receptor complexes through receptor-mediated endocytosis. This process of endocytosis begins when receptors are selectively sequestered into specialized structures on the plasma membrane, termed clathrin-coated pits. These pits are able to recognize receptors through short structures of amino acids in the cytoplasmic domains (12-15). These domains contain specific targeting information. The most common internalization signals described are the tyrosine-based motif and the dileucine motif. The tyrosine-based motif contains a tyrosine residue usually composed of 4 -6 amino acids and is generally formed of NPXY or YXXØ (where X is any amino acid and Ø is a hydrophobic residue; Refs. 16 -19). There are various examples that utilize NPXY or YXXØ motifs for endocytosis. Although the precise mechanism for the sequestration of surface receptors in coated pits is unknown, low density lipoprotein receptors are shown to be endocytosed via their NPXY motif (20). Similarly, numerous other cell surface proteins including epidermal growth factor receptor, insulin receptor family, the ␤-subunits of three integrin receptors, and the amyloid A4 precursor protein utilize the NPXY motif for internalization (20). On the other hand, the transferrin receptor and the asialoglycoprotein receptor endocytose via a YXXØ motif (16,21). It has been demonstrated that a dileucine motif in the intracellular domain of various receptor systems (e.g. interleukin-6 receptor (IL-6R) gp130, granulocyte colony-stimulating factor receptor, epidermal growth factor receptor, growth hormone receptor, human insulin receptor, ␤ 2 -adrenergic receptor, lutropin/choriogonadotropin receptor, and erythropoietin receptor)...

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Identification of Distinct Roles for a Dileucine and a Tyrosine Internalization Motif in the Interleukin (IL)-13 Binding Component IL-13 Receptor α2 Chain

Kawakami

Takeshita

Puri

2001

Journal of Biological Chemistry

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“…The list so far includes: TGF-a, TNF-a, IL-6, EGF, and insulin (all in rat hepatocytes), growth hormone and insulin (in cirrhotic patients), and glucagon (in isolated rat liver plasma membranes) (Table 3) [10,18,62,63,71,91,99]. Remarkably, most of these molecules are known to be internalized by clathrinmediated endocytosis [8,9,23,61,73,80,88,103,105,109]. At present, it is not well established whether the impaired internalization of these various ligands requires ethanol metabolism, but based on the receptor defects described earlier, the prediction is that it does.…”

Section: Cytokines Growth Factors and Hormonesmentioning

confidence: 99%

Alcohol consumption impairs hepatic protein trafficking: mechanisms and consequences

2009

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Alcoholic liver disease is a major biomedical health concern in the United States. Despite considerable research efforts aimed at understanding the progression of the disease, the specific mechanisms leading to alcohol-induced damage remain elusive. Numerous proteins are known to have alcohol-induced alterations in their dynamics. Defining these defects in protein trafficking is an active area of research. In general, two trafficking pathways are affected: transport of newly synthesized secretory or membrane glycoproteins from the Golgi to the basolateral membrane and clathrin-mediated endocytosis from the sinusoidal surface. Both impaired secretion and internalization require ethanol metabolism and are likely mediated by acetaldehyde. Although the mechanisms by which ethanol exposure impairs protein trafficking are not fully understood, recent work implicates alcohol-induced modifications on tubulin or components of the clathrin machinery as potential mediators. Furthermore, the physiological ramifications of impaired protein trafficking are not fully understood. In this review, we will list and discuss the proteins whose trafficking patterns are known to be impaired by ethanol exposure. We will then describe what is known about the possible mechanisms leading to impaired protein trafficking and how disrupted protein trafficking alters liver function and may explain clinical features of the alcoholic patient.

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“…After p27 detection blots were stripped and hybridized with a GAPDH cDNA probe. Fold increase of p27 mRNA normalized according to GAPDH values was calculated using the ImageQuant software after scanning of the blots with a PhosphorImager (Molecular Dynamics) of gp130 (Dittrich et al, 1996;Thiel et al, 1998) and which may account for the lower surface expression of the full-length EG construct compared to the shorter constructs (Figure 3). Studies are in progress to answer this question.…”

Section: Growth Inhibition Of Melanoma Cells By Il-6-type Cytokines Dmentioning

confidence: 99%

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

Heinrich²,

et al. 1999

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Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 melanoma cells. The present study demonstrates that this e ect depends on the activation of STAT transcription factors. We observed a correlation between the extent of growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 receptor or oncostatin M (OSM) and the intensities of STAT3 and STAT1 signals. A truncated chimeric receptor retaining only the membrane-proximal region of gp130, the common signal transducer of IL-6-type cytokines, did neither activate STATs nor mediate growth arrest of stable transfectants. These functions were restored by the addition of short STAT recruitment modules comprising critical tyrosine residues from gp130 (Y767, Y814). A receptor carrying tyrosine module Y759 of gp130 e ectively mediated activation of the phosphatase SHP-2 but did not alter cell growth. Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the inhibitory e ect of OSM and IL-6 in A375 cells. In addition, we have identi®ed the cyclin-dependent kinase inhibitor p27/Kip1 as a novel target to be regulated by IL-6-type cytokines. Stimulation-dependent upregulation of p27 mRNA occurred STAT3-dependently. Also p27 protein accumulated which coincided with the disappearance of hyperphosphorylated retinoblastoma protein in three human melanoma cell lines sensitive to IL-6-type cytokines.

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Internalization of the interleukin 6 signal transducer gp130 does not require activation of the Jak/STAT pathway

Cited by 61 publications

References 41 publications

Identification of Distinct Roles for a Dileucine and a Tyrosine Internalization Motif in the Interleukin (IL)-13 Binding Component IL-13 Receptor α2 Chain

Identification of Distinct Roles for a Dileucine and a Tyrosine Internalization Motif in the Interleukin (IL)-13 Binding Component IL-13 Receptor α2 Chain

Alcohol consumption impairs hepatic protein trafficking: mechanisms and consequences

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

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