This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by You, M.
Right arrow Articles by Feng, G.-S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by You, M.
Right arrow Articles by Feng, G.-S.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 1999, p. 2416-2424, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway

Min You, De-Hua Yu, and Gen-Sheng Feng*

Department of Biochemistry and Molecular Biology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202-5254, and Walther Cancer Institute, Indianapolis, Indiana 46208

Received 6 August 1998/Returned for modification 15 September 1998/Accepted 18 November 1998

Shp-2 is an SH2 domain-containing protein tyrosine phosphatase. Although the mechanism remains to be defined, substantial experimental data suggest that Shp-2 is primarily a positive regulator in cell growth and development. We present evidence here that Shp-2, while acting to promote mitogenic signals, also functions as a negative effector in interferon (IFN)-induced growth-inhibitory and apoptotic pathways. Treatment of mouse fibroblast cells lacking a functional Shp-2 with IFN-alpha or IFN-gamma resulted in an augmented suppression of cell viability compared to that of wild-type cells. To dissect the molecular mechanism, we examined IFN-induced activation of signal transducers and activators of transcription (STATs) by electrophoretic mobility shift assay, using a specific DNA probe (hSIE). The amounts of STAT proteins bound to hSIE upon IFN-alpha or IFN-gamma stimulation were significantly increased in Shp-2-/- cells. Consistently, tyrosine phosphorylation levels of Stat1 upon IFN-gamma treatment and, to a lesser extent, upon IFN-alpha stimulation were markedly elevated in mutant cells. Furthermore, IFN-gamma induced a higher level of caspase 1 expression in Shp-2-/- cells than in wild-type cells. Reintroduction of wild-type Shp-2 protein reversed the hypersensitivity of Shp-2-/- fibroblasts to the cytotoxic effect of IFN-alpha and IFN-gamma . Excessive activation of STATs by IFNs was also diminished in mutant cells in which Shp-2 had been reintroduced. Together, these results establish that Shp-2 functions as a negative regulator of the Jak/STAT pathway. We propose that Shp-2 acts to promote cell growth and survival through two mechanisms, i.e., the stimulation of growth factor-initiated mitogenic pathways and the suppression of cytotoxic effect elicited by cytokines, such as IFNs.

* Corresponding author. Mailing address: Walther Oncology Center, Indiana University School of Medicine, 1044 W. Walnut St., Room 302, Indianapolis, IN 46202-5254. Phone: (317) 274-7515. Fax: (317) 274-7592. E-mail: gfeng{at}iupui.edu.

Molecular and Cellular Biology, March 1999, p. 2416-2424, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Tsai, C.-C., Kai, J.-I., Huang, W.-C., Wang, C.-Y., Wang, Y., Chen, C.-L., Fang, Y.-T., Lin, Y.-S., Anderson, R., Chen, S.-H., Tsao, C.-W., Lin, C.-F. (2009). Glycogen Synthase Kinase-3{beta} Facilitates IFN-{gamma}-Induced STAT1 Activation by Regulating Src Homology-2 Domain-Containing Phosphatase 2. J. Immunol. 183: 856-864 [Abstract] [Full Text]  
  • Bisson, S. A., Page, A.-L., Ganem, D. (2009). A Kaposi's Sarcoma-Associated Herpesvirus Protein That Forms Inhibitory Complexes with Type I Interferon Receptor Subunits, Jak and STAT Proteins, and Blocks Interferon-Mediated Signal Transduction. J. Virol. 83: 5056-5066 [Abstract] [Full Text]  
  • Baron, M., Davignon, J.-L. (2008). Inhibition of IFN-{gamma}-Induced STAT1 Tyrosine Phosphorylation by Human CMV Is Mediated by SHP2. J. Immunol. 181: 5530-5536 [Abstract] [Full Text]  
  • Kontaridis, M. I., Yang, W., Bence, K. K., Cullen, D., Wang, B., Bodyak, N., Ke, Q., Hinek, A., Kang, P. M., Liao, R., Neel, B. G. (2008). Deletion of Ptpn11 (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase and RhoA Signaling Pathways. Circulation 117: 1423-1435 [Abstract] [Full Text]  
  • Gomez, M. A., Li, S., Tremblay, M. L., Olivier, M. (2007). NRAMP-1 Expression Modulates Protein-tyrosine Phosphatase Activity in Macrophages: IMPACT ON HOST CELL SIGNALING AND FUNCTIONS. J. Biol. Chem. 282: 36190-36198 [Abstract] [Full Text]  
  • Ruhul Amin, A.R.M., Uddin Biswas, M. H., Senga, T., Feng, G.-S., Kannagi, R., Agarwal, M. L., Hamaguchi, M. (2007). A role for SHPS-1/SIRP{alpha} in Concanavalin A-dependent production of MMP-9. GENES CELLS 12: 1023-1033 [Abstract] [Full Text]  
  • de Weerd, N. A., Samarajiwa, S. A., Hertzog, P. J. (2007). Type I Interferon Receptors: Biochemistry and Biological Functions. J. Biol. Chem. 282: 20053-20057 [Full Text]  
  • Gao, C., Guo, H., Mi, Z., Grusby, M. J., Kuo, P. C. (2007). Osteopontin Induces Ubiquitin-Dependent Degradation of STAT1 in RAW264.7 Murine Macrophages. J. Immunol. 178: 1870-1881 [Abstract] [Full Text]  
  • Yagi, J., Arimura, Y., Takatori, H., Nakajima, H., Iwamoto, I., Uchiyama, T. (2006). Genetic background influences Th cell differentiation by controlling the capacity for IL-2-induced IL-4 production by naive CD4+ T cells. Int Immunol 18: 1681-1690 [Abstract] [Full Text]  
  • Ke, Y., Lesperance, J., Zhang, E. E., Bard-Chapeau, E. A., Oshima, R. G., Muller, W. J., Feng, G.-S. (2006). Conditional Deletion of Shp2 in the Mammary Gland Leads to Impaired Lobulo-alveolar Outgrowth and Attenuated Stat5 Activation. J. Biol. Chem. 281: 34374-34380 [Abstract] [Full Text]  
  • Gonzalez, R. R., Cherfils, S., Escobar, M., Yoo, J. H., Carino, C., Styer, A. K., Sullivan, B. T., Sakamoto, H., Olawaiye, A., Serikawa, T., Lynch, M. P., Rueda, B. R. (2006). Leptin Signaling Promotes the Growth of Mammary Tumors and Increases the Expression of Vascular Endothelial Growth Factor (VEGF) and Its Receptor Type Two (VEGF-R2). J. Biol. Chem. 281: 26320-26328 [Abstract] [Full Text]  
  • Wang, C.-Z., Su, H.-W., Hsu, Y.-C., Shen, M.-R., Tang, M.-J. (2006). A Discoidin Domain Receptor 1/SHP-2 Signaling Complex Inhibits {alpha}2beta1-Integrin-mediated Signal Transducers and Activators of Transcription 1/3 Activation and Cell Migration. Mol. Biol. Cell 17: 2839-2852 [Abstract] [Full Text]  
  • Leon, C., Nandan, D., Lopez, M., Moeenrezakhanlou, A., Reiner, N. E. (2006). Annexin V Associates with the IFN-{gamma} Receptor and Regulates IFN-{gamma} Signaling. J. Immunol. 176: 5934-5942 [Abstract] [Full Text]  
  • Kim, H. Y., Park, S. J., Joe, E.-h., Jou, I. (2006). Raft-mediated Src Homology 2 Domain-containing Proteintyrosine Phosphatase 2 (SHP-2) Regulation in Microglia. J. Biol. Chem. 281: 11872-11878 [Abstract] [Full Text]  
  • Wormald, S., Zhang, J.-G., Krebs, D. L., Mielke, L. A., Silver, J., Alexander, W. S., Speed, T. P., Nicola, N. A., Hilton, D. J. (2006). The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling. J. Biol. Chem. 281: 11135-11143 [Abstract] [Full Text]  
  • Steiner, E., Holzmann, K., Pirker, C., Elbling, L., Micksche, M., Sutterluty, H., Berger, W. (2006). The major vault protein is responsive to and interferes with interferon-{gamma}-mediated STAT1 signals. J. Cell Sci. 119: 459-469 [Abstract] [Full Text]  
  • Krenz, M., Yutzey, K. E., Robbins, J. (2005). Noonan Syndrome Mutation Q79R in Shp2 Increases Proliferation of Valve Primordia Mesenchymal Cells via Extracellular Signal-Regulated Kinase 1/2 Signaling. Circ. Res. 97: 813-820 [Abstract] [Full Text]  
  • Du, Z., Shen, Y., Yang, W., Mecklenbrauker, I., Neel, B. G., Ivashkiv, L. B. (2005). Inhibition of IFN-{alpha} signaling by a PKC- and protein tyrosine phosphatase SHP-2-dependent pathway. Proc. Natl. Acad. Sci. USA 102: 10267-10272 [Abstract] [Full Text]  
  • Lund, I K, Hansen, J A, Andersen, H S, Moller, N P H, Billestrup, N (2005). Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling. J Mol Endocrinol 34: 339-351 [Abstract] [Full Text]  
  • Guo, J.-T., Hayashi, J., Seeger, C. (2005). West Nile Virus Inhibits the Signal Transduction Pathway of Alpha Interferon. J. Virol. 79: 1343-1350 [Abstract] [Full Text]  
  • Qing, Y., Costa-Pereira, A. P., Watling, D., Stark, G. R. (2005). Role of Tyrosine 441 of Interferon-{gamma} Receptor Subunit 1 in SOCS-1-mediated Attenuation of STAT1 Activation. J. Biol. Chem. 280: 1849-1853 [Abstract] [Full Text]  
  • Arnaud, M., Crouin, C., Deon, C., Loyaux, D., Bertoglio, J. (2004). Phosphorylation of Grb2-Associated Binder 2 on Serine 623 by ERK MAPK Regulates Its Association with the Phosphatase SHP-2 and Decreases STAT5 Activation. J. Immunol. 173: 3962-3971 [Abstract] [Full Text]  
  • Siavash, H., Nikitakis, N.G., Sauk, J.J. (2004). SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION: INSIGHTS INTO THE MOLECULAR BASIS OF ORAL CANCER. CROBM 15: 298-307 [Abstract] [Full Text]  
  • Klampfer, L., Huang, J., Swaby, L.-A., Augenlicht, L. (2004). Requirement of Histone Deacetylase Activity for Signaling by STAT1. J. Biol. Chem. 279: 30358-30368 [Abstract] [Full Text]  
  • Kontaridis, M. I., Eminaga, S., Fornaro, M., Zito, C. I., Sordella, R., Settleman, J., Bennett, A. M. (2004). SHP-2 Positively Regulates Myogenesis by Coupling to the Rho GTPase Signaling Pathway. Mol. Cell. Biol. 24: 5340-5352 [Abstract] [Full Text]  
  • Schroder, K., Hertzog, P. J., Ravasi, T., Hume, D. A. (2004). Interferon-{gamma}: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75: 163-189 [Abstract] [Full Text]  
  • Sakamoto, S., Qin, J., Navarro, A., Gamero, A., Potla, R., Yi, T., Zhu, W., Baker, D. P., Feldman, G., Larner, A. C. (2004). Cells Previously Desensitized to Type 1 Interferons Display Different Mechanisms of Activation of Stat-dependent Gene Expression from Naive Cells. J. Biol. Chem. 279: 3245-3253 [Abstract] [Full Text]  
  • Kim, H. Y., Park, E. J., Joe, E.-h., Jou, I. (2003). Curcumin Suppresses Janus Kinase-STAT Inflammatory Signaling through Activation of Src Homology 2 Domain-Containing Tyrosine Phosphatase 2 in Brain Microglia. J. Immunol. 171: 6072-6079 [Abstract] [Full Text]  
  • Behbod, F., Nagy, Z. S., Stepkowski, S. M., Karras, J., Johnson, C. R., Jarvis, W. D., Kirken, R. A. (2003). Specific Inhibition of Stat5a/b Promotes Apoptosis of IL-2-Responsive Primary and Tumor-Derived Lymphoid Cells. J. Immunol. 171: 3919-3927 [Abstract] [Full Text]  
  • Ruhul Amin, A. R. M., Oo, M. L., Senga, T., Suzuki, N., Feng, G.-S., Hamaguchi, M. (2003). SH2 Domain Containing Protein Tyrosine Phosphatase 2 Regulates Concanavalin A-dependent Secretion and Activation of Matrix Metalloproteinase 2 via the Extracellular Signal-regulated Kinase and p38 Pathways. Cancer Res. 63: 6334-6339 [Abstract] [Full Text]  
  • Lerner-Marmarosh, N., Yoshizumi, M., Che, W., Surapisitchat, J., Kawakatsu, H., Akaike, M., Ding, B., Huang, Q., Yan, C., Berk, B. C., Abe, J.-i. (2003). Inhibition of Tumor Necrosis Factor-{alpha}-Induced SHP-2 Phosphatase Activity by Shear Stress: A Mechanism to Reduce Endothelial Inflammation. Arterioscler. Thromb. Vasc. Bio. 23: 1775-1781 [Abstract] [Full Text]  
  • Kim, H., Suh, J. M., Hwang, E. S., Kim, D. W., Chung, H. K., Song, J. H., Hwang, J. H., Park, K. C., Ro, H. K., Jo, E.-K., Chang, J.-S., Lee, T.-H., Lee, M.-S., Kohn, L. D., Shong, M. (2003). Thyrotropin-Mediated Repression of Class II Trans-Activator Expression in Thyroid Cells: Involvement of STAT3 and Suppressor of Cytokine Signaling. J. Immunol. 171: 616-627 [Abstract] [Full Text]  
  • Chen, Y., Wen, R., Yang, S., Schuman, J., Zhang, E. E., Yi, T., Feng, G.-S., Wang, D. (2003). Identification of Shp-2 as a Stat5A Phosphatase. J. Biol. Chem. 278: 16520-16527 [Abstract] [Full Text]  
  • Prabhakar, S., Qiao, Y., Hoshino, Y., Weiden, M., Canova, A., Giacomini, E., Coccia, E., Pine, R. (2003). Inhibition of Response to Alpha Interferon by Mycobacterium tuberculosis. Infect. Immun. 71: 2487-2497 [Abstract] [Full Text]  
  • Yuan, L., Yu, W.-M., Yuan, Z., Haudenschild, C. C., Qu, C.-K. (2003). Role of SHP-2 Tyrosine Phosphatase in the DNA Damage-induced Cell Death Response. J. Biol. Chem. 278: 15208-15216 [Abstract] [Full Text]  
  • Benekli, M., Baer, M. R., Baumann, H., Wetzler, M. (2003). Signal transducer and activator of transcription proteins in leukemias. Blood 101: 2940-2954 [Abstract] [Full Text]  
  • Wu, T. R., Hong, Y. K., Wang, X.-D., Ling, M. Y., Dragoi, A. M., Chung, A. S., Campbell, A. G., Han, Z.-Y., Feng, G.-S., Chin, Y. E. (2002). SHP-2 Is a Dual-specificity Phosphatase Involved in Stat1 Dephosphorylation at Both Tyrosine and Serine Residues in Nuclei. J. Biol. Chem. 277: 47572-47580 [Abstract] [Full Text]  
  • Yi, T., Pathak, M. K., Lindner, D. J., Ketterer, M. E., Farver, C., Borden, E. C. (2002). Anticancer Activity of Sodium Stibogluconate in Synergy with IFNs. J. Immunol. 169: 5978-5985 [Abstract] [Full Text]  
  • Saenger, P. (2002). Noonan Syndrome--Certitude Replaces Conjecture. J. Clin. Endocrinol. Metab. 87: 3527-3528 [Full Text]  
  • Kim, H., Lee, T.-H., Hwang, Y. S., Bang, M. A., Kim, K. H., Suh, J. M., Chung, H. K., Yu, D.-Y., Lee, K.-K., Kwon, O-Y., Ro, H. K., Shong, M. (2001). Methimazole As an Antioxidant and Immunomodulator in Thyroid Cells: Mechanisms Involving Interferon-gamma Signaling and H2O2 Scavenging. Mol. Pharmacol. 60: 972-980 [Abstract] [Full Text]  
  • Wang, K. S., Zorn, E., Ritz, J. (2001). Specific down-regulation of interleukin-12 signaling through induction of phospho-STAT4 protein degradation. Blood 97: 3860-3866 [Abstract] [Full Text]  
  • Patil, S., Newman, D. K., Newman, P. J. (2001). Platelet endothelial cell adhesion molecule-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood 97: 1727-1732 [Abstract] [Full Text]  
  • You, M., Flick, L. M., Yu, D., Feng, G.-S. (2001). Modulation of the Nuclear Factor {kappa}b Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor. JEM 193: 101-110 [Abstract] [Full Text]  
  • Stofega, M. R., Herrington, J., Billestrup, N., Carter-Su, C. (2000). Mutation of the SHP-2 Binding Site in Growth Hormone (GH) Receptor Prolongs GH-Promoted Tyrosyl Phosphorylation of GH Receptor, JAK2, and STAT5B. Mol. Endocrinol. 14: 1338-1350 [Abstract] [Full Text]  
  • Saharinen, P., Takaluoma, K., Silvennoinen, O. (2000). Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain. Mol. Cell. Biol. 20: 3387-3395 [Abstract] [Full Text]  
  • Franchimont, D., Galon, J., Gadina, M., Visconti, R., Zhou, Y.-J., Aringer, M., Frucht, D. M., Chrousos, G. P., O'Shea, J. J. (2000). Inhibition of Th1 Immune Response by Glucocorticoids: Dexamethasone Selectively Inhibits IL-12-Induced Stat4 Phosphorylation in T Lymphocytes. J. Immunol. 164: 1768-1774 [Abstract] [Full Text]  
  • Ward, A. C., Touw, I., Yoshimura, A. (2000). The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood 95: 19-29 [Full Text]  
  • Nguyen, V.-A. T., Gao, B. (1999). Cross-talk between alpha 1B-Adrenergic Receptor (alpha 1BAR) and Interleukin-6 (IL-6) Signaling Pathways. ACTIVATION OF alpha 1BAR INHIBITS IL-6-ACTIVATED STAT3 IN HEPATIC CELLS BY A p42/44 MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT MECHANISM. J. Biol. Chem. 274: 35492-35498 [Abstract] [Full Text]  
  • Pluskota, E., Chen, Y., D'Souza, S. E. (2000). Src Homology Domain 2-containing Tyrosine Phosphatase 2 Associates with Intercellular Adhesion Molecule 1 to Regulate Cell Survival. J. Biol. Chem. 275: 30029-30036 [Abstract] [Full Text]  
  • Miyakawa, Y., Rojnuckarin, P., Habib, T., Kaushansky, K. (2001). Thrombopoietin Induces Phosphoinositol 3-Kinase Activation through SHP2, Gab, and Insulin Receptor Substrate Proteins in BAF3 Cells and Primary Murine Megakaryocytes. J. Biol. Chem. 276: 2494-2502 [Abstract] [Full Text]  
  • dos Santos, C. M. A., van Kerkhof, P., Strous, G. J. (2001). The Signal Transduction of the Growth Hormone Receptor Is Regulated by the Ubiquitin/Proteasome System and Continues After Endocytosis. J. Biol. Chem. 276: 10839-10846 [Abstract] [Full Text]  
  • Tanuma, N., Nakamura, K., Shima, H., Kikuchi, K. (2000). Protein-tyrosine Phosphatase PTPepsilon C Inhibits Jak-STAT Signaling and Differentiation Induced by Interleukin-6 and Leukemia Inhibitory Factor in M1 Leukemia Cells. J. Biol. Chem. 275: 28216-28221 [Abstract] [Full Text]  
  • Bjorbak, C., Buchholz, R. M., Davis, S. M., Bates, S. H., Pierroz, D. D., Gu, H., Neel, B. G., Myers, M. G. Jr., Flier, J. S. (2001). Divergent Roles of SHP-2 in ERK Activation by Leptin Receptors. J. Biol. Chem. 276: 4747-4755 [Abstract] [Full Text]  
  • Ali, S., Ali, S. (2000). Recruitment of the Protein-tyrosine Phosphatase SHP-2 to the C-terminal Tyrosine of the Prolactin Receptor and to the Adaptor Protein Gab2. J. Biol. Chem. 275: 39073-39080 [Abstract] [Full Text]  
  • Gamero, A. M., Larner, A. C. (2001). Vanadate Facilitates Interferon alpha -mediated Apoptosis That Is Dependent on the Jak/Stat Pathway. J. Biol. Chem. 276: 13547-13553 [Abstract] [Full Text]  
  • Gregorieff, A., Pyronnet, S., Sonenberg, N., Veillette, A. (2000). Regulation of SOCS-1 Expression by Translational Repression. J. Biol. Chem. 275: 21596-21604 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»