The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase.

Haspel, R. L.; Salditt‐Georgieff, M.; Darnell, J. E.

doi:10.1002/j.1460-2075.1996.tb01016.x

Cited by 312Cytokine Signaling Pathways and InteractionsProtein Tyrosine Phosphatasesinterferon and immune responses

The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase.

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Haspel, R. L., Salditt‐Georgieff, M., Darnell, J. E.·1996·The EMBO Journal

DOI 10.1002/j.1460-2075.1996.tb01016.xPMC PMC452449

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Abstract

After interferon-gamma (IFN-gamma) treatment of cells the appearance of tyrosine phosphorylated Stat1 in the nucleus was maximal within 20-30 min, remained for 2-2.5 h and activated molecules disappeared by 4 h. In the absence of continued signaling from the receptor (imposed by staurosporine treatment) previously activated Stat1 disappeared completely within 60 min, implying continuous generation and removal of active molecules during extended IFN-gamma treatment. Proteasome inhibitors prolonged the time of activation of Stat1 by prolonging signaling from the receptor but not by blocking removal of already activated Stat1 molecules. By analyzing with 35S labeling the distribution of total Stat1 and activated Stat1, we concluded that the Stat1 molecules promptly cycle into the nucleus as tyrosine phosphorylated molecules and later return quantitatively to the cytoplasm as non-phosphorylated molecules. Therefore, the removal of the activated Stat1 molecules from the nucleus appears not to be proteolytic but must depend on a protein tyrosine phosphatase(s).

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Stat1 has a slow turnover time (t1/2 > 8 h) and its dephosphorylation is rapid (t1/2 < 15 min).
“Given that Stat1 has a slow turnover time (t 1/2 > 8 h; Lee et al. 1997) but dephosphorylation is rapid (t 1/2 < 15 min; Haspel et al. 1996), we wanted to determine how long Stat1 molecules remained nuclear.”
From DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1 (2003) · cites this paper as Haspel et al. 1996

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Stats: Multifaceted Regulators of Transcription
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Vaccinia Virus Blocks Gamma Interferon Signal Transduction: Viral VH1 Phosphatase Reverses Stat1 Activation
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Nucleocytoplasmic translocation of Stat1 is regulated by a leucine-rich export signal in the coiled-coil domain
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Cytokine Signaling
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A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b
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Retracted
A Janus Kinase Inhibitor, JAB, Is an Interferon-γ–Inducible Gene and Confers Resistance to Interferons
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Cellular Physiology of STAT3: Where’s the Cytoplasmic Monomer?*
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Implications of an antiparallel dimeric structure of nonphosphorylated STAT1 for the activation–inactivation cycle
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Cytosolic Tyrosine Dephosphorylation of STAT5
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Dephosphorylation of phosphotyrosine on STAT1 dimers requires extensive spatial reorientation of the monomers facilitated by the N-terminal domainPreprint
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Inactivation of the Fanconi Anemia Group C Gene Augments Interferon-γ–Induced Apoptotic Responses in Hematopoietic Cells
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DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1
Meyer, T., Marg, A., Lemke, P., Wiesner, B., & Vinkemeier, U. (2003) · Genes & Development · doi:10.1101/gad.268003 · Cited by 161 · see citing works
“Loss of DNA binding was also described to cause defects in nuclear accumulation, although conflicting data with various DNAbinding mutants were reported (Herrington et al. 1999; McBride et al. 2000; Melén et al. 2001; Lillemeier et al. 2001).”
Weapons of STAT destruction
Horvath, C. M. (2004) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.2004.04425.x · Cited by 161 · see citing works
ERK1 and ERK2 Activate CCAAAT/Enhancer-binding Protein-β-dependent Gene Transcription in Response to Interferon-γ
Hu, J., Roy, S. K., Shapiro, P. S., Rodig, S. J., Reddy, S. P., Platanias, L. C., Schreiber, R. D., & Kalvakolanu, D. V. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m004885200 · Cited by 153 · see citing works
Functional Interaction of STAT3 Transcription Factor with the Cell Cycle Inhibitor p21 WAF1/CIP1/SDI1 *
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A cytomegaloviral protein reveals a dual role for STAT2 in IFN-γ signaling and antiviral responses
Zimmermann, A., Trilling, M., Wagner, M., Wilborn, M., Bubić, I., Jonjić, S., Koszinowski, U. H., & Hengel, H. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041401 · Cited by 150 · see citing works
Local Type I IFN Receptor Signaling Protects against Virus Spread within the Central Nervous System
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Protein Kinase B (c-Akt), Phosphatidylinositol 3-Kinase, and STAT5 Are Activated by Erythropoietin (EPO) in HCD57 Erythroid Cells But Are Constitutively Active in an EPO-Independent, Apoptosis-Resistant Subclone (HCD57-SREI Cells)
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STATs as critical mediators of signal transduction and transcription: lessons learned from STAT5
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Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription
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Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling
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Selective STAT Protein Degradation Induced by Paramyxoviruses Requires both STAT1 and STAT2 but Is Independent of Alpha/Beta Interferon Signal Transduction
Parisien, J.-P., Lau, J. F., Rodriguez, J. J., Ulane, C. M., & Horvath, C. M. (2002) · Journal of Virology · doi:10.1128/jvi.76.9.4190-4198.2002 · Cited by 136 · see citing works
ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis
Ma, K., Ivanov, V. N., Dong, J., & Ronai, Z. A. (2003) · Oncogene · doi:10.1038/sj.onc.1206598 · Cited by 132 · see citing works
Paramyxovirus strategies for evading the interferon response
Gotoh, B., Komatsu, T., Takeuchi, K., & Yokoo, J. (2002) · Reviews in Medical Virology · doi:10.1002/rmv.357 · Cited by 131 · see citing works
Nucleocytoplasmic shuttling of STAT transcription factors
Meyer, T., & Vinkemeier, U. (2004) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.2004.04423.x · Cited by 132 · see citing works
A Drosophila PIAS homologue negatively regulates stat92E
Betz, A., Lampen, N., Martinek, S., Young, M. W., & Darnell, J. E., Jr. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171302098 · Cited by 132 · see citing works
Paradigm shifts in the cell biology of STAT signaling
Sehgal, P. B. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.07.003 · Cited by 130 · see citing works
Cytokines and STAT Signaling
Schindler, C., & Strehlow, I. (1999) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60111-8 · Cited by 129 · see citing works
Involvement of Proteasomes in Regulating Jak-STAT Pathways upon Interleukin-2 Stimulation
Yu, C., & Burakoff, S. J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.22.14017 · Cited by 129 · see citing works
STATs get their move on
Reich, N. C. (2013) · JAK-STAT · doi:10.4161/jkst.27080 · Cited by 125 · see citing works
Identification of Shp-2 as a Stat5A Phosphatase
Chen, Y., Wen, R., Yang, S., Schuman, J., Zhang, E. E., Yi, T., Feng, G., & Wang, D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210572200 · Cited by 124 · see citing works
Glucocorticoid Receptor/Signal Transducer and Activator of Transcription 5 (STAT5) Interactions Enhance STAT5 Activation by Prolonging STAT5 DNA Binding and Tyrosine Phosphorylation
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STAT1-induced Apoptosis Is Mediated by Caspases 2, 3, and 7
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Different protein turnover of interleukin‐6‐type cytokine signalling components
Siewert, E., Müller‐Esterl, W., Starr, R., Heinrich, P. C., & Schaper, F. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00719.x · Cited by 121 · see citing works
A small amphipathic α‐helical region is required for transcriptional activities and proteasome‐dependent turnover of the tyrosine‐phosphorylated Stat5
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Amino-terminal Signal Transducer and Activator of Transcription (STAT) Domains Regulate Nuclear Translocation and STAT Deactivation
Strehlow, I., & Schindler, C. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.43.28049 · Cited by 120 · see citing works
Phototherapy: How does UV work?
Weichenthal, M., & Schwarz, T. (2005) · Photodermatology Photoimmunology & Photomedicine · doi:10.1111/j.1600-0781.2005.00173.x · Cited by 119 · see citing works
A Nuclear Protein Tyrosine Phosphatase TC-PTP Is a Potential Negative Regulator of the PRL-Mediated Signaling Pathway: Dephosphorylation and Deactivation of Signal Transducer and Activator of Transcription 5a and 5b by TC-PTP in Nucleus
Aoki, N., & Matsuda, T. (2002) · Molecular Endocrinology · doi:10.1210/mend.16.1.0761 · Cited by 119 · see citing works
Retracted
STAT Signaling in the Pathogenesis and Treatment of Cancer
Frank, D. A. (1999) · Molecular Medicine · doi:10.1007/bf03403538 · Cited by 116 · see citing works
Getting the message across, STAT! Design principles of a molecular signaling circuit
Vinkemeier, U. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200407163 · Cited by 118 · see citing works
All Four Sendai Virus C Proteins Bind Stat1, but only the Larger Forms also Induce Its Mono-ubiquitination and Degradation
Garcin, D., Marq, J., Strähle, L., Mercier, P. L., & Kolakofsky, D. (2002) · Virology · doi:10.1006/viro.2001.1342 · Cited by 116 · see citing works
STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the α2-macroglobulin genePreprint
Lerner, L. R., Henriksen, M. A., Zhang, X., & Darnell, J. E., Jr. (2003) · Genes & Development · doi:10.1101/gad.1135003 · Cited by 115 · see citing works
Signal transducers and activators of transcription as regulators of growth, apoptosis and breast development
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Differential Effects of Prolactin andsrc/abl Kinases on the Nuclear Translocation of STAT5B and STAT5A
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Transcription factor activity of STAT proteins: structural requirements and regulation by phosphorylation and interacting proteins
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Identification of novel direct Stat3 target genes for control of growth and differentiation
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Alternate interferon signaling pathways
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Composition and Assembly of STAT-Targeting Ubiquitin Ligase Complexes: Paramyxovirus V Protein Carboxyl Terminus Is an Oligomerization Domain
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Protein tyrosine phosphatases as wardens of STAT signaling
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IL‐10 attenuates IFN‐α‐activated STAT1 in the liver: involvement of SOCS2 and SOCS3
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Inactivation of the JAK-STAT Pathway
Haspel, R. L. (2025) · Digital Commons - RU (Rockefeller University) · doi:10.48496/x721-yg74 · Cited by 2 · see citing works
Self-citation
A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1
Haspel, R. L., & Darnell, J. E. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.18.10188 · Cited by 203 · see citing works
Self-citation
Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase
ten Hoeve, J., de Jesus Ibarra-Sanchez, M., Fu, Y., Zhu, W., Tremblay, M., David, M., & Shuai, K. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.16.5662-5668.2002 · Cited by 507 · see citing works
Enhancement of Antiproliferative Activity of Gamma Interferon by the Specific Inhibition of Tyrosine Dephosphorylation of Stat1
Shuai, K., Liao, J., & Song, M. M. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4932 · Cited by 151 · see citing works
Nuclear export block of tyrosine-phosphorylated STAT1 facilitates rapid responsiveness to interferon-γ stimuli at the expense of signal strength
Meyer, T., Lamprecht, F., Begitt, A., Höfer, T., & Vinkemeier, U. (2026) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2026.195151

Authors: Haspel, R. L., Salditt‐Georgieff, M., & Darnell, J. E.
Affiliations: Rockefeller University (US)
ORCID: Haspel, R. L.
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 1996-11-01
Volume: 15
Issue: 22
Pages: 6262-6268
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1002/j.1460-2075.1996.tb01016.x
PMC: PMC452449
OpenAlex: W1702674772
Cited by: 312
References: 41
Citations by year: 2026: 2 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 12 · 2013: 9 · 2012: 6
FWCI: 12.59
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (GM07739)
National Institute of Allergy and Infectious Diseases (R01AI032489, AI32489, AI324420)
Topics: Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords: STAT1, tyrosine phosphorylation, protein tyrosine phosphatase, interferon-gamma signaling, nuclear translocation, proteasome inhibitors, staurosporine, receptor signaling, transcription factor regulation
MeSH terms: Acetylcysteine, Cell Nucleus, Cysteine Endopeptidases, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Enzyme Inhibitors, Fibroblasts, Humans, Interferon-gamma, Leupeptins, Multienzyme Complexes, Nuclear Proteins, Phosphorylation, Vanadates, Blotting, Western, Signal Transduction, Trans-Activators, Protein Tyrosine Phosphatases, Receptors, Interferon, Phosphotyrosine, Staurosporine, Proteasome Endopeptidase Complex, STAT1 Transcription Factor

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The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase.

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