Defective gp130-mediated Signal Transducer and Activator of Transcription (STAT) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation

doi:10.1084/jem.194.2.189

Published online 16 July 2001. doi:10.1084/jem.194.2.189

This Article

Full Text

Full Text (PDF, 759K)

PPT slides of all figures

Alert me when this article is cited

Citation Map

Services

Email this article

Similar articles in this journal

Similar articles in PubMed

Alert me to new content in the JEM

Download to citation manager

Citing Articles

Citing Articles via HighWire

Citing Articles via CrossRef

Citing Articles via Google Scholar

Google Scholar

Articles by Ernst, M.

Articles by Dunn, A. R.

Search for Related Content

PubMed

PubMed Citation

Articles by Ernst, M.

Articles by Dunn, A. R.

Pubmed/NCBI databases

Gene	GEO Profiles
HomoloGene	UniGene
Substance via MeSH

Social Bookmarking

What's this?

© The Rockefeller University Press, 0022-1007/2001/7/189/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 2, July 16, 2001 189-204

Original Article

Defective gp130-mediated Signal Transducer and Activator of Transcription (STAT) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation

Matthias Ernst^a, Melissa Inglese^a, Paul Waring^c, Ian K. Campbell^b, Shisan Bao^d, Fiona J. Clay^a, Warren S. Alexander^b, Ian P. Wicks^b, David M. Tarlinton^b, Ulrike Novak^e, Joan K. Heath^a, and Ashley R. Dunn^a
^a Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, VIC 3050, Australia
^b The Walter and Eliza Hall Institute, PO Royal Melbourne Hospital, VIC 3050, Australia
^c Department of Pathology, Peter MacCallum Institute, East Melbourne VIC 3002, Australia
^d Department of Pathology, University of Sydney, Sydney, NSW 2006, Australia
^e Department of Surgery, The University of Melbourne Parkville, VIC 3052, Australia

Correspondence to: Matthias Ernst, Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, VIC 3050, Australia. Tel:61-3-3941-3149 Fax:61-3-9341-3191 E-mail:matthias.ernst{at}ludwig.edu.au.

The receptor subunit gp130 transduces multiple cell type–specificactivities of the leukemia inhibitory factor (LIF)/interleukin(IL)-6 family of cytokines through the signal transducer andactivator of transcription (STAT) and src homology 2 domain–bearingprotein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To defineSTAT-dependent physiological responses, we generated mice witha COOH-terminal gp130^STAT "knock-in" mutation which deletedall STAT-binding sites. gp130^STAT mice phenocopyed mice deficientfor IL-6 (impaired humoral and mucosal immune and hepatic acutephase responses) and LIF (failure of blastocyst implantation).However, unlike mice with null mutations in any of the componentsin the gp130 signaling pathway, gp130^STAT mice also displayedgastrointestinal ulceration and a severe joint disease withfeatures of chronic synovitis, cartilaginous metaplasia, anddegradation of the articular cartilage. Mitogenic hyperresponsivenessof synovial cells to the LIF/IL-6 family of cyto-kines was causedby sustained gp130-mediated SHP-2/ras/Erk activation due toimpaired STAT-mediated induction of suppressor of cytokine signaling(SOCS) proteins which normally limits gp130 signaling. Therefore,the joint pathology in gp130^STAT mice is likely to arise fromthe disturbance of the otherwise balanced activation of theSHP-2/ras/Erk and STAT signaling cascades emanating from gp130.

Key Words: infertility, signal transduction, STAT, interleukin, gene targeting

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

Kondoh, E., Okamoto, T., Higuchi, T., Tatsumi, K., Baba, T., Murphy, S. K., Takakura, K., Konishi, I., Fujii, S. (2009). Stress affects uterine receptivity through an ovarian-independent pathway. Hum Reprod 24: 945-953 [Abstract] [Full Text]
Steinberg, G. R., Watt, M. J., Ernst, M., Birnbaum, M. J., Kemp, B. E., Jorgensen, S. B. (2009). Ciliary Neurotrophic Factor Stimulates Muscle Glucose Uptake by a PI3-Kinase-Dependent Pathway That Is Impaired With Obesity. Diabetes 58: 829-839 [Abstract] [Full Text]
Nelson, S. M., Greer, I. A. (2008). The potential role of heparin in assisted conception. Hum Reprod Update 14: 623-645 [Abstract] [Full Text]
Fielding, C. A., McLoughlin, R. M., McLeod, L., Colmont, C. S., Najdovska, M., Grail, D., Ernst, M., Jones, S. A., Topley, N., Jenkins, B. J. (2008). IL-6 Regulates Neutrophil Trafficking during Acute Inflammation via STAT3. J. Immunol. 181: 2189-2195 [Abstract] [Full Text]
Fitzgerald, J. S., Poehlmann, T. G., Schleussner, E., Markert, U. R. (2008). Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3). Hum Reprod Update 0: dmn010v1-10 [Abstract] [Full Text]
Dierssen, U., Beraza, N., Lutz, H. H., Liedtke, C., Ernst, M., Wasmuth, H. E., Trautwein, C. (2008). Molecular Dissection of gp130-dependent Pathways in Hepatocytes during Liver Regeneration. J. Biol. Chem. 283: 9886-9895 [Abstract] [Full Text]
White, C. A., Zhang, J.-G., Salamonsen, L. A., Baca, M., Fairlie, W. D., Metcalf, D., Nicola, N. A., Robb, L., Dimitriadis, E. (2007). From the Cover: Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy. Proc. Natl. Acad. Sci. USA 104: 19357-19362 [Abstract] [Full Text]
Rahman, A. (2007). Regulators of cytokine signalling in rheumatoid arthritis. Rheumatology (Oxford) 46: 1745-1746 [Full Text]
Campbell, E.A., O'Hara, L., Catalano, R.D., Sharkey, A.M., Freeman, T.C., Johnson, M. H. (2006). Temporal expression profiling of the uterine luminal epithelium of the pseudo-pregnant mouse suggests receptivity to the fertilized egg is associated with complex transcriptional changes. Hum Reprod 21: 2495-2513 [Abstract] [Full Text]
Forrai, A., Boyle, K., Hart, A. H., Hartley, L., Rakar, S., Willson, T. A., Simpson, K. M., Roberts, A. W., Alexander, W. S., Voss, A. K., Robb, L. (2006). Absence of Suppressor of Cytokine Signalling 3 Reduces Self-Renewal and Promotes Differentiation in Murine Embryonic Stem Cells. Stem Cells 24: 604-614 [Abstract] [Full Text]
Song, H., Lim, H. (2006). Evidence for heterodimeric association of leukemia inhibitory factor (LIF) receptor and gp130 in the mouse uterus for LIF signaling during blastocyst implantation. Reproduction 131: 341-349 [Abstract] [Full Text]
Kimber, S. J (2005). Leukaemia inhibitory factor in implantation and uterine biology. Reproduction 130: 131-145 [Abstract] [Full Text]
Villarino, A. V., Larkin, J. III, Saris, C. J. M., Caton, A. J., Lucas, S., Wong, T., de Sauvage, F. J., Hunter, C. A. (2005). Positive and Negative Regulation of the IL-27 Receptor during Lymphoid Cell Activation. J. Immunol. 174: 7684-7691 [Abstract] [Full Text]
Catalano, R. D., Johnson, M. H., Campbell, E. A., Charnock-Jones, D. S., Smith, S. K., Sharkey, A. M. (2005). Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception. Proc. Natl. Acad. Sci. USA 102: 8585-8590 [Abstract] [Full Text]
Dorval-Coiffec, I., Delcros, J.-G., Hakovirta, H., Toppari, J., Jegou, B., Piquet-Pellorce, C. (2005). Identification of the Leukemia Inhibitory Factor Cell Targets Within the Rat Testis. Biol. Reprod. 72: 602-611 [Abstract] [Full Text]
Nozaki, I., Lunz, J. G. III, Specht, S., Park, J.-I., Giraud, A. S., Murase, N., Demetris, A. J. (2004). Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree. Am. J. Pathol. 165: 1907-1920 [Abstract] [Full Text]
Artis, D., Villarino, A., Silverman, M., He, W., Thornton, E. M., Mu, S., Summer, S., Covey, T. M., Huang, E., Yoshida, H., Koretzky, G., Goldschmidt, M., Wu, G. D., de Sauvage, F., Miller, H. R. P., Saris, C. J. M., Scott, P., Hunter, C. A. (2004). The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity. J. Immunol. 173: 5626-5634 [Abstract] [Full Text]
Zhao, L., Hart, S., Cheng, J., Melenhorst, J. J., Bierie, B., Ernst, M., Stewart, C., Schaper, F., Heinrich, P. C., Ullrich, A., Robinson, G. W., Hennighausen, L. (2004). Mammary Gland Remodeling Depends on gp130 Signaling through Stat3 and MAPK. J. Biol. Chem. 279: 44093-44100 [Abstract] [Full Text]
Barton, B. E., Murphy, T. F., Shu, P., Huang, H. F., Meyenhofen, M., Barton, A. (2004). Novel single-stranded oligonucleotides that inhibit signal transducer and activator of transcription 3 induce apoptosis in vitro and in vivo in prostate cancer cell lines. Molecular Cancer Therapeutics 3: 1183-1191 [Abstract] [Full Text]
Sherwin, J. R. A., Freeman, T. C., Stephens, R. J., Kimber, S., Smith, A. G., Chambers, I., Smith, S. K., Sharkey, A. M. (2004). Identification of Genes Regulated by Leukemia-Inhibitory Factor in the Mouse Uterus at the Time of Implantation. Mol. Endocrinol. 18: 2185-2195 [Abstract] [Full Text]
Teng, C.-B., Diao, H.-L., Ma, H., Cong, J., Yu, H., Ma, X.-H., Xu, L.-B., Yang, Z.-M. (2004). Signal transducer and activator of transcription 3 (Stat3) expression and activation in rat uterus during early pregnancy. Reproduction 128: 197-205 [Abstract] [Full Text]
Dey, S. K., Lim, H., Das, S. K., Reese, J., Paria, B. C., Daikoku, T., Wang, H. (2004). Molecular Cues to Implantation. Endocr. Rev. 25: 341-373 [Abstract] [Full Text]
Daikoku, T., Song, H., Guo, Y., Riesewijk, A., Mosselman, S., Das, S. K., Dey, S. K. (2004). Uterine Msx-1 and Wnt4 Signaling Becomes Aberrant in Mice with the Loss of Leukemia Inhibitory Factor or Hoxa-10: Evidence for a Novel Cytokine-Homeobox-Wnt Signaling in Implantation. Mol. Endocrinol. 18: 1238-1250 [Abstract] [Full Text]
Jenkins, B. J., Grail, D., Inglese, M., Quilici, C., Bozinovski, S., Wong, P., Ernst, M. (2004). Imbalanced gp130-Dependent Signaling in Macrophages Alters Macrophage Colony-Stimulating Factor Responsiveness via Regulation of c-fms Expression. Mol. Cell. Biol. 24: 1453-1463 [Abstract] [Full Text]
Chen, B., Zhang, D., Pollard, J. W. (2003). Progesterone Regulation of the Mammalian Ortholog of Methylcitrate Dehydratase (Immune Response Gene 1) in the Uterine Epithelium during Implantation through the Protein Kinase C Pathway. Mol. Endocrinol. 17: 2340-2354 [Abstract] [Full Text]
Molyneaux, K. A., Schaible, K., Wylie, C. (2003). GP130, the shared receptor for the LIF/IL6 cytokine family in the mouse, is not required for early germ cell differentiation, but is required cell-autonomously in oocytes for ovulation. Development 130: 4287-4294 [Abstract] [Full Text]
Bode, J. G., Schweigart, J., Kehrmann, J., Ehlting, C., Schaper, F., Heinrich, P. C., Haussinger, D. (2003). TNF-{alpha} Induces Tyrosine Phosphorylation and Recruitment of the Src Homology Protein-Tyrosine Phosphatase 2 to the gp130 Signal-Transducing Subunit of the IL-6 Receptor Complex. J. Immunol. 171: 257-266 [Abstract] [Full Text]
Wuestefeld, T., Klein, C., Streetz, K. L., Betz, U., Lauber, J., Buer, J., Manns, M. P., Muller, W., Trautwein, C. (2003). Interleukin-6/Glycoprotein 130-dependent Pathways Are Protective during Liver Regeneration. J. Biol. Chem. 278: 11281-11288 [Abstract] [Full Text]
Legendre, F., Dudhia, J., Pujol, J.-P., Bogdanowicz, P. (2003). JAK/STAT but Not ERK1/ERK2 Pathway Mediates Interleukin (IL)-6/Soluble IL-6R Down-regulation of Type II Collagen, Aggrecan Core, and Link Protein Transcription in Articular Chondrocytes. ASSOCIATION WITH A DOWN-REGULATION OF SOX9 EXPRESSION. J. Biol. Chem. 278: 2903-2912 [Abstract] [Full Text]
Lehmann, U., Schmitz, J., Weissenbach, M., Sobota, R. M., Hortner, M., Friederichs, K., Behrmann, I., Tsiaris, W., Sasaki, A., Schneider-Mergener, J., Yoshimura, A., Neel, B. G., Heinrich, P. C., Schaper, F. (2003). SHP2 and SOCS3 Contribute to Tyr-759-dependent Attenuation of Interleukin-6 Signaling through gp130. J. Biol. Chem. 278: 661-671 [Abstract] [Full Text]
Atsumi, T., Ishihara, K., Kamimura, D., Ikushima, H., Ohtani, T., Hirota, S., Kobayashi, H., Park, S.-J., Saeki, Y., Kitamura, Y., Hirano, T. (2002). A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis. JEM 196: 979-990 [Abstract] [Full Text]
Paria, B. C., Reese, J., Das, S. K., Dey, S. K. (2002). Deciphering the Cross-Talk of Implantation: Advances and Challenges. Science 296: 2185-2188 [Abstract] [Full Text]
Deon, D., Ahmed, S., Tai, K., Scaletta, N., Herrero, C., Lee, I.-H., Krause, A., Ivashkiv, L. B. (2001). Cross-Talk Between IL-1 and IL-6 Signaling Pathways in Rheumatoid Arthritis Synovial Fibroblasts. J. Immunol. 167: 5395-5403 [Abstract] [Full Text]