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See detailInferring the metabolism of human orphan metabolites from their metabolic network context affirms human gluconokinase activity.
Rolfsson, Ottar; Paglia, Giuseppe; Magnusdottir, Manuela et al

in Biochemical Journal (2013), 449(2), 427-435

Metabolic network reconstructions define metabolic information within a target organism and can therefore be used to address incomplete metabolic information. In the present study we used a computational ... [more ▼]

Metabolic network reconstructions define metabolic information within a target organism and can therefore be used to address incomplete metabolic information. In the present study we used a computational approach to identify human metabolites whose metabolism is incomplete on the basis of their detection in humans but exclusion from the human metabolic network reconstruction RECON 1. Candidate solutions, composed of metabolic reactions capable of explaining the metabolism of these compounds, were then identified computationally from a global biochemical reaction database. Solutions were characterized with respect to how metabolites were incorporated into RECON 1 and their biological relevance. Through detailed case studies we show that biologically plausible non-intuitive hypotheses regarding the metabolism of these compounds can be proposed in a semi-automated manner, in an approach that is similar to de novo network reconstruction. We subsequently experimentally validated one of the proposed hypotheses and report that C9orf103, previously identified as a candidate tumour suppressor gene, encodes a functional human gluconokinase. The results of the present study demonstrate how semi-automatic gap filling can be used to refine and extend metabolic reconstructions, thereby increasing their biological scope. Furthermore, we illustrate how incomplete human metabolic knowledge can be coupled with gene annotation in order to prioritize and confirm gene functions. [less ▲]

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See detailThe role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling
Fischer, P.; Lehmann, U.; Sobota, R. M. et al

in Biochemical Journal (2004), 378(Pt 2), 449-60

The immediate early response of cells treated with IL-6 (interleukin-6) is the activation of the signal transducer and activator of transcription (STAT)3. The Src homology domain 2 (SH2)-containing ... [more ▼]

The immediate early response of cells treated with IL-6 (interleukin-6) is the activation of the signal transducer and activator of transcription (STAT)3. The Src homology domain 2 (SH2)-containing protein tyrosine phosphatase SHP2 and the feedback inhibitor SOCS3 (suppressor of cytokine signalling) are potent inhibitors of IL-6 signal transduction. Impaired function of SOCS3 or SHP2 leads to enhanced and prolonged IL-6 signalling. The inhibitory function of both proteins depends on their recruitment to the tyrosine motif 759 within glycoprotein gp130. In contrast to inactivation, desensitization of signal transduction is regarded as impaired responsiveness due to prestimulation. Usually, after activation the sensing receptor becomes inactivated by modifications such as phosphorylation, internalization or degradation. We designed an experimental approach which allows discrimination between desensitization and inactivation of IL-6 signal transduction. We observed that pre-stimulation with IL-6 renders cells less sensitive to further stimulation with IL-6. After several hours, the cells become sensitive again. We show that not only signal transduction through previously activated receptors is affected by desensitization but signalling through receptors which were not targeted by the first stimulation was also attenuated ( trans -desensitization). Interestingly, in contrast to inhibition, desensitization does not depend on the presence of functional SHP2. Furthermore, cells lacking SOCS3 show constitutive STAT3 activation which is not affected by pre-stimulation with IL-6. All these observations suggest that desensitization and inhibition of signalling are mechanistically distinct. [less ▲]

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See detailPrinciples of interleukin (IL)-6-type cytokine signalling and its regulation
Heinrich, P. C.; Behrmann, Iris UL; Haan, Serge UL et al

in Biochemical Journal (2003), 374(Pt 1), 1-20

The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important ... [more ▼]

The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed. [less ▲]

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See detailA single amino acid substitution (Trp(666)-->Ala) in the interbox1/2 region of the interleukin-6 signal transducer gp130 abrogates binding of JAK1, and dominantly impairs signal transduction
Haan, Claude UL; Hermanns, H. M.; Heinrich, P. C. et al

in Biochemical Journal (2001), 349(Pt 1), 261-6

gp130 is the common signal-transducing receptor chain of interleukin (IL)-6-type cytokines. Here we describe, for the first time, a single amino acid substitution (Trp(666)-->Ala) in the membrane-proximal ... [more ▼]

gp130 is the common signal-transducing receptor chain of interleukin (IL)-6-type cytokines. Here we describe, for the first time, a single amino acid substitution (Trp(666)-->Ala) in the membrane-proximal interbox1/2 region that abrogates activation of STAT (signal transducer and activator of transcription) transcription factors and the proliferative response of pro-B-cell transfectants. Moreover, association of the Janus kinase JAK1 is prevented. No signalling of heterodimeric IL-5 receptor (IL-5R)/gp130 chimaeras occurs in COS-7 cells, even when only a single cytoplasmic chain of a gp130 dimer contains the Trp(666)Ala mutation, indicating that it acts dominantly. [less ▲]

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See detailStructural requirements of the interleukin-6 signal transducer gp130 for its interaction with Janus kinase 1: the receptor is crucial for kinase activation
Haan, Claude UL; Heinrich, P. C.; Behrmann, Iris UL

in Biochemical Journal (2001), 361(Pt 1), 105-11

We analysed the interaction of gp130, the common signal-transducing receptor chain of interleukin (IL)-6 type cytokines, with Jak1, the Janus family kinase which is crucial for signal transduction of this ... [more ▼]

We analysed the interaction of gp130, the common signal-transducing receptor chain of interleukin (IL)-6 type cytokines, with Jak1, the Janus family kinase which is crucial for signal transduction of this group of cytokines. With a truncated chimaeric IL-5Rbeta-gp130 receptor expressed in COS-7 cells, we show that the membrane-proximal 69 amino acids are sufficient to mediate Jak1 binding and activation. Deletion of box2 drastically reduced binding of endogenous, but not of overexpressed, Jak1. Several point mutations in the membrane-proximal region of gp130 (W652A, P671/P672A, F676A, Y683F, where W, A, P, F and Y are tryptophan, alanine, proline, phenylalanine and tyrosine) did not affect Jak1 association. However, stimulation of chimaeric receptors with the mutations P671/P672A and F676A in the interbox1/box2 region resulted in a reduced activation of STAT (signal transducer and activator of transcription) transcription factors. Most importantly, signalling by the receptor with the box1 mutation W652A was totally abrogated. Although this mutation did not affect Jak1 association, stimulation-dependent phosphorylation of Jak1 was prevented. The W652 mutation acts dominantly, since no signalling occured even when only a single cytoplasmic chain of a gp130 dimer contained the mutation. Our data demonstrate that the mere proximity of Jaks in an activated receptor complex is not sufficient to mediate their activation. Rather, it seems that parts of the receptor, including the box1 region, are involved in positioning Jaks correctly so that ligand-induced receptor dimerization and reorientation can lead to their mutual activation and subsequently to downstream signalling events. [less ▲]

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See detailMitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells
Kortylewski, M.; Heinrich, P. C.; Kauffmann, M. E. et al

in Biochemical Journal (2001), 357(Pt 1), 297-303

The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated protein kinase (ERK)1 and ERK2, involved in regulating cell growth and differentiation, are constitutively active in A375 and ... [more ▼]

The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated protein kinase (ERK)1 and ERK2, involved in regulating cell growth and differentiation, are constitutively active in A375 and WM239 human melanoma cells. Using PD098059, an inhibitor of MAPK kinase (MEK), we investigated the role of persistently activated ERK1/2 in cell growth. The inhibition of MAPK activity induced a dose-dependent growth arrest in G(0)/G(1) phase. Correspondingly, we observed the up-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27/Kip1 and hypophosphorylation of the retinoblastoma protein. Further studies showed that PD098059 treatment significantly decreased Cdk2 kinase activity, most probably owing to an augmented level of p27/Kip1 associated with cyclin E-Cdk2 complexes. The accumulation of p27/Kip1 protein in A375 cells was attributed to its increased stability. Our findings suggest that constitutively active ERK1/2 kinases contribute to the growth of melanoma cells by negative regulation of the p27/Kip1 inhibitor. [less ▲]

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See detailCytoplasmic STAT proteins associate prior to activation
Haan, Serge UL; Kortylewski, M.; Behrmann, Iris UL et al

in Biochemical Journal (2000), 345 Pt 3

The commonly accepted model of STAT factor activation at the cytoplasmic part of the receptor assumes that signal transducers and activators of transcription (STATs) are recruited from a cytoplasmic pool ... [more ▼]

The commonly accepted model of STAT factor activation at the cytoplasmic part of the receptor assumes that signal transducers and activators of transcription (STATs) are recruited from a cytoplasmic pool of monomeric STAT proteins. Based on a previous observation that non-phosphorylated STAT3-Src homology 2 domains dimerize in vitro, we investigated whether the observed dimerization is of physiological relevance within the cellular context. We show that STAT1 and STAT3 are pre-associated in non-stimulated cells. Apparently, these complexes are not able to translocate into the nucleus. We provide evidence that the event of STAT activation is more complex than previously assumed. [less ▲]

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See detailIdentification of a Leu-lle internalization motif within the cytoplasmic domain of the leukaemia inhibitory factor receptor
Thiel, S.; Behrmann, Iris UL; Timmermann, A. et al

in Biochemical Journal (1999), 339 (Pt 1)

Leukaemia inhibitory factor (LIF) signals via a heterodimeric receptor complex comprised of the LIF receptor (LIFR) and the interleukin (IL)-6 signal transducer gp130. Upon binding to its cognate receptor ... [more ▼]

Leukaemia inhibitory factor (LIF) signals via a heterodimeric receptor complex comprised of the LIF receptor (LIFR) and the interleukin (IL)-6 signal transducer gp130. Upon binding to its cognate receptor LIF is internalized. In this study, we show that the LIFR is endocytosed independently of gp130. By using a heterochimaeric receptor system we identified a dileucine-based internalization motif within the cytoplasmic domain of the LIFR. Our findings suggest that a heterodimeric LIFR/gp130 complex and homodimeric gp130/gp130 complex are endocytosed via distinct internalization signals. [less ▲]

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See detailInternalization of the interleukin 6 signal transducer gp130 does not require activation of the Jak/STAT pathway
Thiel, S.; Behrmann, Iris UL; Dittrich, E. et al

in Biochemical Journal (1998), 330 (Pt 1)

Signalling receptors often undergo receptor-mediated endocytosis. In many cases this internalization is stimulated by ligand binding and activation of intrinsic receptor tyrosine kinases, resulting in a ... [more ▼]

Signalling receptors often undergo receptor-mediated endocytosis. In many cases this internalization is stimulated by ligand binding and activation of intrinsic receptor tyrosine kinases, resulting in a receptor down-regulation. We have analysed whether internalization of the interleukin 6 signal transducer gp130 is dependent on the activation of receptor-associated Jak kinases. By using a chimaeric receptor system we found that receptor mutants that lack box1 and therefore are not capable of activating Jak and signal transducer and activator of transcription (STAT) proteins are still endocytosed efficiently. A chimaeric receptor with the recently identified dileucine internalization motif being replaced by two alanine residues was not efficiently internalized but still capable of recruiting STATs. Furthermore an antagonistic antibody that inhibits the signalling of all interleukin-6-type cytokines via gp130 was internalized as efficiently as an agonistic one that activates the Jak/STAT pathway. Our findings suggest that the endocytosis of gp130 is signal-independent. [less ▲]

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See detailInterleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway
Heinrich, P. C.; Behrmann, Iris UL; Müller-Newen, G. et al

in Biochemical Journal (1998), 334 (Pt 2)

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1 ... [more ▼]

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals. [less ▲]

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See detailNatural polyamines stimulate G-proteins
Bueb, Jean-Luc UL; Da Silva, A.; Mousli, M. et al

in Biochemical Journal (1992), 282 (Pt 2)

The natural polyamines spermine and spermidine, the biosynthetic precursor putrescine and their analogues cadaverine and tyramine stimulate the GTPase activity of purified GTP-binding proteins (Go/Gi ... [more ▼]

The natural polyamines spermine and spermidine, the biosynthetic precursor putrescine and their analogues cadaverine and tyramine stimulate the GTPase activity of purified GTP-binding proteins (Go/Gi) from calf brain reconstituted into phospholipid vesicles. The order of potency was spermine greater than spermidine greater than putrescine = cadaverine greater than tyramine. The physiological relevance of this observation was assessed, showing the same order of potency of polyamines in the stimulation of peritoneal and tracheal rat mast cells. The activation of rat mast cells by polyamines was inhibited by benzalkonium chloride or by a 2 h pretreatment of the cells with pertussis toxin. The increase in inositol phosphates evoked by polyamines was also inhibited by pertussis toxin. Therefore we propose that intracellular polyamines might control the basal level of second messengers and modulate extracellular signals transduced through G-protein-coupled receptors. [less ▲]

Detailed reference viewed: 67 (0 UL)