Nucleocytoplasmic shuttling of persistently activated STAT3
Abstract
Persistent activation of the transcription factor STAT3 has been detected in many types of cancer and plays an important role in tumor progression, immune evasion and metastasis. To analyze persistent STAT3 activation we coexpressed STAT3 with v-Src. We found that tyrosine phosphorylation of STAT3 by v-Src is independent of Janus kinases (Jaks), the canonical activators of STATs. The STAT3-induced feedback inhibitor, suppressor of cytokine signaling 3 (SOCS3), did not interfere with STAT3 activation by v-Src. However, the protein inhibitor of activated STAT3 (PIAS3) suppressed gene induction by persistently activated STAT3. We measured nucleocytoplasmic shuttling of STAT3 in single cells by bleaching the YFP moiety of double-labelled STAT3-CFP-YFP in the cytoplasm. Analysis of the subcellular distribution of CFP and YFP fluorescence over time by mathematical modeling and computational parameter estimation revealed that activated STAT3 shuttles more rapidly than non-activated STAT3. Inhibition of exportin-1-mediated nuclear export slowed down nucleocytoplasmic shuttling of v-Src-activated STAT3 resulting in reduced tyrosine phosphorylation, decreased induction of STAT3 target genes and increased apoptosis. We propose passage of persistently activated STAT3 through the nuclear pore complex as a new target for intervention in cancer.
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There has been increasing evidence of basal nucleocytoplasmic shuttling of STAT3.
“As there has been increasing evidence of basal nucleocytoplasmic shuttling of STAT3 [6,41–43]”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [41]
Cites
Principles of interleukin (IL)-6-type cytokine signalling and its regulation
HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F. (2003) · Biochemical Journal · doi:10.1042/bj20030407 · Cited by 3,272 · cited 2× · see citing works
“The family of IL-6-type cytokines that signal through the cytokine receptor gp130 are the most potent physiological activators of STAT3 (Heinrich et al., 2003).”
BackgroundSelf-citationSpecific Inhibition of Stat3 Signal Transduction by PIAS3
Chung, C. D., Liao, J., Liu, B., Rao, X., Jay, P., Berta, P., & Shuai, K. (1997) · Science · doi:10.1126/science.278.5344.1803 · Cited by 980 · see citing works
Lütticken, C., Wegenka, U. M., Yuan, J., Buschmann, J., Schindler, C., Ziemiecki, A., Harpur, A. G., Wilks, A. F., Yasukawa, K., Taga, T., et al. (1994) · Science · doi:10.1126/science.8272872 · Cited by 814 · cited 1× · see citing works
“Activated STAT3 dimers accumulate in the nucleus, where they induce target genes (Lütticken et al., 1994; Stahl et al., 1994).”
BackgroundSelf-citationSchmitz, J., Weissenbach, M., Haan, S., Heinrich, P. C., & Schaper, F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.17.12848 · Cited by 388 · cited 2× · see citing works
“SOCS3 inhibits Jak1 at the receptor leading to attenuation of Jak1/STAT3 signalling (Nicholson et al., 2000; Schmitz et al., 2000).”
BackgroundSelf-citationActivation and Association of Stat3 with Src in v-Src-Transformed Cell Lines
Cao, X., Tay, A., Guy, G. R., & Tan, Y. H. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.4.1595 · Cited by 359 · see citing works
Haspel, R. L., Salditt‐Georgieff, M., & Darnell, J. E. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01016.x · Cited by 312 · see citing works
Validating Stat3 in cancer therapy
Darnell, J. E. (2005) · Nature Medicine · doi:10.1038/nm0605-595 · Cited by 307 · see citing works
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Ng, I. H. W., Ng, D. C. H., Jans, D. A., & Bogoyevitch, M. A. (2012) · Biochemical Journal · doi:10.1042/bj20120941 · Cited by 63 · see citing works
“As there has been increasing evidence of basal nucleocyto-plasmic shuttling of STAT3 [6,41–43], and that basal STAT3 has been shown to have transcriptional activity under basal conditions [44,45], we explored whether this phenomenon of cross-regulation could be attributed to changes in expression…”
BackgroundMartincuks, A., Andryka, K., Küster, A., Schmitz-Van de Leur, H., Komorowski, M., & Müller-Newen, G. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.01.006 · Cited by 45 · see citing works
Self-citationSobotta, S., Raue, A., Huang, X., Vanlier, J., Jünger, A., Bohl, S., Albrecht, U., Hahnel, M. J., Wolf, S., Mueller, N. S., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00775 · Cited by 28 · see citing works
- Authors
- Herrmann, A., Vogt, M., Mönnigmann, M., Clahsen, T., Sommer, U., Haan, S., Poli, V., Heinrich, P. C., & Müller-Newen, G.
- Affiliations
- Universitätsklinikum Aachen (DE)
- Lehrstuhl für Prozesstechnik, RWTH Aachen, Templergraben 55, 52056 Aachen, Germany
- University of Turin (IT)
- Institut für Biochemie, Universitätsklinikum RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2007-09-15
- Volume
- 120
- Issue
- 18
- Pages
- 3249-3261
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2081221906
- Cited by
- 94
- References
- 7
- Citations by year
- 2024: 2 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 8 · 2017: 6 · 2016: 6 · 2015: 4 · 2014: 8 · 2013: 5 · 2012: 9
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- STAT3, nucleocytoplasmic shuttling, v-Src, tyrosine phosphorylation, Janus kinase, SOCS3, PIAS3, CRM1, nuclear export, nuclear pore complex, mathematical modeling, apoptosis, cancer
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Exportin 1 Protein, Animals, Chlorocebus aethiops, Cytoplasm, Humans, Models, Biological, Phosphorylation, Oncogene Protein pp60(v-src), Receptors, Cytoplasmic and Nuclear, Molecular Chaperones, COS Cells, Active Transport, Cell Nucleus, Nuclear Pore, Karyopherins, NIH 3T3 Cells, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Protein Inhibitors of Activated STAT, Mice
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