PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells

Sun, Shishinn; Steinberg, Bettie M.

doi:10.1099/0022-1317-83-7-1651

Cited by 101Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesPI3K/AKT/mTOR signaling in cancer

PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells

Sun, Shishinn, Steinberg, Bettie M.·2002·Journal of General Virology

DOI 10.1099/0022-1317-83-7-1651

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Abstract

Laryngeal papillomas are caused by infection of the laryngeal epithelium by human papillomavirus type 6 or type 11 (HPV-6/-11). Previous studies in our laboratory have demonstrated an increase in PI3 kinase levels in papilloma tissue. However, activation of the downstream effector of PI3 kinase, protein kinase B (PKB/Akt), was reduced. This observation was explained by the elevated expression of the phosphatase and tensin homologue (PTEN), a recently characterized tumour suppressor, in papilloma tissue. Recent investigation of the possible functional roles of PTEN during papilloma development has now indicated that the level of tyrosine(705)-phosphorylated signal transducer and activator of transcription 3 [PTyr(705)STAT3] could be inversely correlated to that of PTEN as well. In vitro phosphatase assays suggested the presence of an increased level of a PTyr(705)STAT3 phosphatase in papilloma extract. Immunodepletion of PTEN from papilloma extracts resulted in a reduction of the PTyr(705)STAT3 phosphatase activity. Transfection of PTEN cDNA into HeLa cells attenuated STAT3 phosphorylation at Tyr(705) in a dose-dependent manner. This attenuation of STAT3 phosphorylation was independent of the STAT3 kinase. Interestingly, introduction of a lipid phosphatase mutant of PTEN (G129E) resulted in heightened PTyr(705)STAT3 phosphatase activity, relative to that obtained from wild-type PTEN transfection. These data indicate that PTEN negatively regulates STAT3 activation in HPV-infect…

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PTEN acts as a negative regulator of STAT3 through its protein phosphatase activity, but this modulation is context dependent and PTEN can also positively regulate STAT3 in certain tumors such as gliomas.
“Other phosphatases have been implicated in the modulation of STAT3 signaling, for example, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which has both lipid and protein phosphatase activity, has been shown to act as a negative regulator of STAT3 (Sun and Steinberg, 2002; Mukhopadhyay et al., 2010), where its protein phosphatase activity negatively affects phosphorylation of”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Sun and Steinberg, 2002
HTLV-I, Epstein-Barr virus and papilloma virus activate STAT3 and NF-κB.
“Both hepatitis B and hepatitis C viruses, which induce hepatitis and cause hepatocellular carcinoma, activate STAT3 (328–330), while HTLV-I, Epstein–Barr virus and papilloma virus activate STAT3 and NF-κB (311, 331, 332).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [332]

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Background
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BackgroundInfluential
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Background
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Background
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Background
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Self-citation
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Background
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Background
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Background
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Retracted
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Background
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“, 2002), PTEN (Sun and Steinberg, 2002), PTP-1D (Gunaje and Bhat, 2001), CD45 (Irie-Sasaki et al.”
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“PTEN is reported to act as a negative controller of STAT3 activation [34].”
Background
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“Western Blot Analysis Pulverized frozen tissues were extracted as previously described (8).”
BackgroundMethodSelf-citation
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Self-citation
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“We also found evidence that inhibition of STAT3 activation is linked to the induction of a PTP by GA. Numerous PTPs have been implicated in STAT3 signaling, including SHP-1 (39), SHP-2 (40), TC-PTP (41), PTEN (42), PTP-1D (43), CD45 (43), and PTP-e.”
Retracted
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“The function of PTEN and p53 in STAT3 activation has already been studied in previous investigations 13,19 .”
STAT3 signaling is induced by intercellular adhesion in squamous cell carcinoma cells
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“Interestingly, integrin α1 ligation has been shown to activate PTEN [34], which is known to dephosphorylate STAT3-Y705 [35].”
Background
The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells
Liu, C.-Y., Huang, T.-T., Chu, P.-Y., Huang, C.-T., Lee, C.-H., Wang, W.-L., Lau, K.-Y., Tsai, W.-C., Chao, T.-I., Su, J.-C., et al. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.114 · Cited by 40 · see citing works
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“For example, Sun and Steinberg [44] reported that tyrosine phosphorylation of Stat3 (Tyr705) was inversely correlated with expression of PTEN in vitro.”
Background
Requirement of STAT3 Activation for Differentiation of Mucosal Stratified Squamous Epithelium
Wu, R., Sun, S., & Steinberg, B. (2003) · Molecular Medicine · doi:10.2119/2003-00001.wu · Cited by 39
“Papillomas show reduced activation of protein kinase B (PKB or Akt) (10) and reduced levels of phosphorylated STAT3 due to overexpression of the tumor suppressor, PTEN (11).”
BackgroundResultInfluentialSelf-citation
Blockage of STAT3 Signaling Pathway by Morusin Induces Apoptosis and Inhibits Invasion in Human Pancreatic Tumor Cells
Kim, C., Kim, J. H., Oh, E., Nam, D., Lee, S.-G., Lee, J., Kim, S.-H., Shim, B., & Ahn, K. (2016) · Pancreas · doi:10.1097/mpa.0000000000000496 · Cited by 37 · see citing works
p53 regulates cytoskeleton remodeling to suppress tumor progression
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STAT3 dictates β-cell apoptosis by modulating PTEN in streptozocin-induced hyperglycemia
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The phosphoinositide 3-kinase signalling pathway as a therapeutic target in squamous cell carcinoma of the head and neck
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“In papillomas, PTEN is also a negative regulator of signal transducter and activator of translation (STAT)-3 activation, interesting as a possible a point of convergence in SCCHN cell signalling [136,137].”
Background
Regulatory T‐cell stability and functional plasticity in health and disease
Malviya, V., Yshii, L., Junius, S., Garg, A. D., Humblet‐Baron, S., & Schlenner, S. (2022) · Immunology and Cell Biology · doi:10.1111/imcb.12613 · Cited by 36 · see citing works
“to negatively regulate STAT3 activity to limit TH17driven disease.(178,179) STAT3 activity is further restrained”
Background
Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges
Arshad, S., Naveed, M., Ullia, M., Javed, K., Butt, A. J., Khawar, M., & Amjad, F. (2020) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2018-0160 · Cited by 36 · see citing works
Critical Role of Caveolin-1 Loss/Dysfunction in Pulmonary Hypertension
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“STAT3 activation and β-catenin localization [104,105].”
Augmenting regulatory T cells: new therapeutic strategy for rheumatoid arthritis
Zhang, J., Liu, H.-J., Chen, Y.-H., Liu, H., Zhang, S., Yin, G., & Xie, Q.-B. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1312919 · Cited by 25 · see citing works
β-Arrestin 2 is a mediator of GnRH-(1-5) signaling in immortalized GnRH neurons.
Larco, D. O., Semsarzadeh, N., Cho-Clark, M. J., Mani, S., & Wu, T. J. (2013) · Endocrinology · doi:10.1210/en.2013-1286 · Cited by 25 · see citing works
“PTEN has been shown to negatively regulate the phosphorylation of STAT3 (41), and therefore we examined whether PTEN is involved in our model.”
Background
Pak1 and Pak2 are activated in recurrent respiratory papillomas, contributing to one pathway of Rac1-mediated COX-2 expression
Wu, R., Abramson, A. L., Symons, M., & Steinberg, B. M. (2010) · International Journal of Cancer · doi:10.1002/ijc.25226 · Cited by 25
Self-citation
Fluacrypyrim, a novel STAT3 activation inhibitor, induces cell cycle arrest and apoptosis in cancer cells harboring constitutively‐active STAT3
Yu, Z.-Y., Huang, R., Xiao, H., Sun, W., Shan, Y., Wang, B., Zhao, T., Dong, B., Zhao, Z.-H., Liu, X.-L., et al. (2010) · International Journal of Cancer · doi:10.1002/ijc.25169 · Cited by 25 · see citing works
“Numerous PTPs, such as SHP-1, SHP-2 and PTEN, have been implicated in STAT3 signaling.(44,49,50) Some reported anticancer agents, such as ursolic acid(51) and CDDO-imidazolide,(52) have been shown to suppress STAT3 phosphorylation via induction of the SHP-1 expression.”
Background
Hypoxia-induced pulmonary hypertension and chronic lung disease: caveolin-1 dysfunction an important underlying feature
Huang, J., Frid, M., Gewitz, M., Fallon, J., Brown, D., Krafsur, G., Stenmark, K., & Mathew, R. (2019) · Pulmonary Circulation · doi:10.1177/2045894019837876 · Cited by 24
“PTEN has also been shown to have an inverse relationship with -catenin21 and it negatively regulates STAT3 and its activation; importantly, membrane localization of PTEN is considered responsible for the inactivation of STAT3.”
BackgroundInfluential
PTEN interacts with metal-responsive transcription factor 1 and stimulates its transcriptional activity.
Lin, M.-C., Liu, Y.-C., Tam, M. F., Lu, Y.-J., Hsieh, Y.-T., & Lin, L.-Y. (2012) · Biochemical Journal · doi:10.1042/bj20111257 · Cited by 22 · see citing works
Role of STAT3 and NRF2 in Tumors: Potential Targets for Antitumor Therapy
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Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials
Shima, K., Kaufhold, I., Eder, T., Käding, N., Schmidt, N., Ogunsulire, I. M., Deenen, R., Köhrer, K., Friedrich, D., Isay, S. E., et al. (2021) · mBio · doi:10.1128/mbio.00023-21 · Cited by 17 · see citing works
PC cell-derived growth factor overexpression promotes proliferation and survival of laryngeal carcinoma
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Molecular cloning and characterization of PTEN in the orange-spotted grouper (Epinephelus coioides).
Luo, S.-W., Wang, W.-N., Xie, R.-C., Xie, F.-X., Kong, J., Xiao, Y.-C., Huang, D., Sun, Z.-M., Liu, Y., & Wang, C.-C. (2016) · Fish and Shellfish Immunology · doi:10.1016/j.fsi.2016.10.007 · Cited by 15
“Thus, PTEN, a natural antagonist of PI3K/Akt, can execute its negative regulatory role in PI3K/Akt signaling cascade [13], and thereby block the DNA binding activity of NF-kB by disrupting the phosphorylation via PI3K/Akt signaling [100], regulate negatively Stat3 signaling cascade by reducing Stat3 phosphorylation [1…”
Microcystin-LR promotes migration via the cooperation between microRNA-221/PTEN and STAT3 signal pathway in colon cancer cell line DLD-1.
Ren, Y.-D., Yang, M.-L., Ma, R., Gong, Y., Zou, Y., Wang, T., & Wu, J.-Z. (2019) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2018.09.065 · Cited by 14 · see citing works
Regulation Of Rod Photoreceptor Differentiation By STAT3 Is Controlled By A Tyrosine Phosphatase
Pinzon-Guzman, C., Xing, T.-S., Zhang, S. S., & Barnstable, C. (2014) · Journal of Molecular Neuroscience · doi:10.1007/s12031-014-0397-1 · Cited by 14 · see citing works
“Among these are the phosphatase and tensin homologue (PTEN), protein-tyrosine phosphatase 1B (PTP1B), and the SH2- containing phosphatases 1 and 2 (Shp1 and Shp2) (Sun and Steinberg 2002; Yasukawa et al. 2000; Shuai and Liu 2003).”
HPV16 E2-mediated potentiation of NF-κB activation induced by TNF-α involves parallel activation of STAT3 with a reduction in E2-induced apoptosis
Prabhavathy, D., Prabhakar, B., & Karunagaran, D. (2014) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-014-2083-6 · Cited by 14 · see citing works
Altered T cell differentiation and Notch signaling induced by the ectopic expression of keratin K10 in the epithelial cells of the thymus
Santos, M., Río, P., Ruíz, S., Martínez‐Palacio, J., Segrelles, C., Lara, M. F., Segovia, J. C., & Paramio, J. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20406 · Cited by 14
3,3′-Diindolylmethane improves antitumor immune responses of PD-1 blockade via inhibiting myeloid-derived suppressor cells
Sun, Q., Xiao, L., Cui, Z., Yang, Y.-P., Ma, J., Huang, Z., Zhang, J.-F., & Chen, J.-N. (2022) · Chinese Medicine · doi:10.1186/s13020-022-00638-z · Cited by 13 · see citing works
“As PTEN and PIAS3 has been proved to be the negative regulators of STAT3, an essential transcriptional factor during the MDSC’s life cycle, our experimental data further confirmed that miR-21 targeting PTEN and PIAS3, which play a synergistic role in suppressing STAT3 activation during the process of inducing function…”
Background
The tyrosine phosphatase PTPN14 inhibits the activation of STAT3 in PEDV infected Vero cells.
Huang, H., Li, Y.-T., Li, D.-L., Wang, L., Jiao, W.-Q., Bai, Y.-L., & Zhang, G.-P. (2022) · Veterinary Microbiology · doi:10.1016/j.vetmic.2022.109391 · Cited by 11 · see citing works
Albendazole Exhibits Anti-Neoplastic Actions against Gastric Cancer Cells by Affecting STAT3 and STAT5 Activation by Pleiotropic Mechanism(s)
Yang, M.-H., Ha, I. J., Um, J., & Ahn, K. (2021) · Biomedicines · doi:10.3390/biomedicines9040362 · Cited by 11 · see citing works
Accelerated cancer aggressiveness by viral oncomodulation: New targets and newer natural treatments for cancer control and treatment
Blaylock, R. L. (2019) · Surgical Neurology International · doi:10.25259/sni_361_2019 · Cited by 10 · see citing works
“A number of tumor viruses can activate the STAT3 pathway, including HCMV, EBV, HPV, HTLV virus, and hepatitis B virus [Figure 6].[113,138,183,204] STAT3 can also be activated by other noninfectious stresses, including direct lipopolysaccharide stimulation through toll-like receptor 4 immune activation, UV light induct…”
Background
ATM inhibition prevents interleukin-6 from contributing to the proliferation of glioblastoma cells after ionizing radiation
Lim, Y., Quek, H., Offenhäuser, C., Fazry, S., Boyd, A., Lavin, M., Roberts, T., & Day, B. (2018) · Journal of Neuro-Oncology · doi:10.1007/s11060-018-2838-0 · Cited by 11 · see citing works
Phosphatidylinositol 3-kinase regulates early differentiation in human laryngeal keratinocytes
Dackour, R., Carter, T., & Steinberg, B. (2005) · In vitro Cellular & Developmental Biology-Animal · doi:10.1290/0501003.1 · Cited by 8
“The PTEN also reduces levels of activated STAT-3 (Sun and Steinberg, 2002), and STAT-3 contributes to regulation of mucosal keratinocyte K13 expression (Wu et al., 2003).”
BackgroundSelf-citation
Association of Single Nucleotide Polymorphism rs1053004 in Signal Transducer and Activator of Transcription 3 (STAT3) with Susceptibility to Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B.
Chanthra, N., Payungporn, S., Chuaypen, N., Pinjaroen, N., Poovorawan, Y., & Tangkijvanich, P. (2015) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2015.16.12.5069 · Cited by 8
“It has been shown that several tumor-related viruses, including HBV, are related to the activation of STAT3 (Migone et al., 1995; Sun and Steinberg, 2002; Choudhari et al., 2007; Muromoto et al., 2009).”
Background
Flavipin from fungi as a potential inhibitor of rheumatoid arthritis signaling molecules
Ahmed, E. A., Alzahrani, A. M., Abdelsalam, S. A., & Ibrahim, H.-I. M. (2024) · Inflammopharmacology · doi:10.1007/s10787-024-01429-8 · Cited by 4 · see citing works
Endothelial Dysfunction and Disruption in Pulmonary Hypertension
Mathew, R. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.92177 · Cited by 6 · see citing works
Decreased STAT3 Phosphorylation Mediates Cell Swelling in Ammonia-Treated Astrocyte Cultures
Jayakumar, A., Curtis, K. M., Panickar, K., Shamaladevi, N., & Nörenberg, M. (2016) · Biology · doi:10.3390/biology5040048 · Cited by 4 · see citing works
“Phosphatases such as protein tyrosi e phosphatase 1B (PTP1B), Src homology phosphatases (SHPs), pr tein phosphatase-2 (PP2A), PTPRT-1 and osphatase and tensin homol g (PTEN), are ll well-known to dephosphorylate serine or tyrosine resi ues f STAT3 [30–33].”
Background
Clinical analysis of microdebrider removal of recurrent respiratory papilloma: A report of 33 cases
Lei, W.-B., Su, Z.-Z., Wen, W., Chai, L., Jiang, A.-Y., & Li, J. (2006) · doi:10.1007/s11805-006-0116-y · Cited by 4
Aberrant STAT3 activation and overproduction of IL-21 in systemic lupus erythematosus: role of miR-155 and miR-21 in target genes SOCS1, PTEN and PIAS3
Espinoza-García, N., Palafox-Sánchez, C., Arellano, A. R. D., Salazar-Camarena, D., Félix-Murray, K. R., Marín-Rosales, M., Ortiz-Lazareno, P., Vega-Cornejo, G., Armendáriz-Borunda, J., & Muñóz-Valle, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1664409 · Cited by 2 · see citing works
Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples
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PTEN regulation in virus-associated cancers.
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Historical Development of STAT3 Inhibitors and Early Results in Clinical Trials
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Downregulated PTEN and aberrant JAK–STAT signal pathway in essential thrombocythemia patients
Luo, L., Liu, X.-Y., Shen, H., Zhang, H., Shang, Y.-X., Zhang, X., & Zhang, D.-L. (2025) · Frontiers in Hematology · doi:10.3389/frhem.2025.1479185
PI3K/PTEN signaling in liver diseases
Fort, A., Calo, N., Portius, D., Bourgoin, L., Peyrou, M., & Foti, M. (2015) · doi:10.1002/9781118663387.ch21 · Cited by 1 · see citing works
表皮角化細胞のStat3 シグナル(後編)
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STAT3 activation in recurrent respiratory papillomatosis.
Patel, N., Hansen, A., Merati, A., & Kerschner, J. (2004) · Archives of Otolaryngology - Head and Neck Surgery · doi:10.1001/archotol.130.9.1043
“This is in contrast to a previous study that suggested that the level of phosphorylated STAT3 was reduced in papilloma tissue in the presence of constitutively activated epidermal growth factor receptor.(15) The differences between the 2 studies may be due to a difference in methods.”
Result

Authors: Sun, S., & Steinberg, B. M.
Affiliations: Northwell Health (US)
ORCID: Steinberg, Bettie M.
Venue: Journal of General Virology
Publisher: Microbiology Society
Published: 2002-07-01
Volume: 83
Issue: 7
Pages: 1651-1658
ISSN: 0022-1317 (ISSN-L)
1465-2099
DOI: 10.1099/0022-1317-83-7-1651
OpenAlex: W2145360255
Cited by: 101
References: 0
Citations by year: 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 7 · 2021: 3 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 6 · 2013: 5 · 2012: 4
FWCI: 1.48
Type: journal article
Language: en
Open access: closed
Locations: Journal of General Virology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Deafness and Other Communication Disorders (P50DC000203, P50 DC00203)
Topics: Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: PTEN, STAT3, human papillomavirus, recurrent respiratory papillomatosis, HPV 6, HPV 11, phosphatase activity, PI3-kinase, Akt, tumour suppressor, epithelial differentiation
MeSH terms: Cell Extracts, DNA-Binding Proteins, Epithelium, HeLa Cells, Humans, Laryngeal Neoplasms, Larynx, Mutation, Papilloma, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphotransferases, Transfection, Tumor Cells, Cultured, Trans-Activators, Down-Regulation, Genes, Tumor Suppressor, DNA, Complementary, Phosphotyrosine, Tumor Suppressor Proteins, Papillomaviridae, STAT3 Transcription Factor, PTEN Phosphohydrolase

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PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells

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