CoChat
Sign Up
Cited by 59Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesReceptor Mechanisms and Signaling

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

Open access
Mertens, Claudia, Haripal, Bhagwattie, Klinge, Sebastian, Darnell, James E.·2015·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1515876112PMC PMC4672786
Open this paper in CoChat — free accountOpen PDF

Abstract

Significance: Examination of mutants in linker domain of STAT3 suggests contacts with both the DNA binding and SH2 domains that may cause structural changes and affect pSTAT3-dependent transcription, opening the possibility of new targets for drug inhibition of pSTAT3.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1515876112

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Studies investigating the impact of disease-causing mutations on STAT3 suggest that there are long-range communications between domains of STAT3, implying that STAT3 activity may be subject to allosteric modulation.

    “Studies investigating the impact of disease-causing mutations on STAT3 suggest that there are long-range communications between domains of STAT3, implying that STAT3 activity may be subject to allosteric modulation (Zhang et al., 2000; Mertens et al., 2015; Namanja et al., 2016).”

    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 Mertens et al., 2015

    The paper’s opening summary and Discussion report functional interactions between STAT3 domains and propose that altering those interactions could inhibit STAT3 activity. However, the mutations tested in this study were introduced experimentally; the paper does not establish that they are disease-causing mutations. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 41

  1. Stark GR, Darnell JE, Jr (2012) The JAK-STAT pathway at twenty. Immunity 36(4):503-514.
  2. Chen X, et al. (1998) Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 93(5):827-839.
  3. Becker S, Groner B, Müller CW (1998) Three-dimensional structure of the Stat3beta homodimer bound to DNA. Nature 394(6689):145-151.
  4. Neculai D, et al. (2005) Structure of the unphosphorylated STAT5a dimer. J Biol Chem 280(49):40782-40787.
  5. Vinkemeier U, Moarefi I, Darnell JE, Jr, Kuriyan J (1998) Structure of the amino-terminal protein interaction domain of STAT-4. Science 279(5353):1048-1052.
  6. Chen X, et al. (2003) A reinterpretation of the dimerization interface of the N-terminal domains of STATs. Protein Sci 12(2):361-365.
  7. Wen Z, Zhong Z, Darnell JE, Jr (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82(2):241-250.
  8. Levine M, Cattoglio C, Tjian R (2014) Looping back to leap forward: Transcription enters a new era. Cell 157(1):13-25.
  9. Allis CD, Capparros M-L, Jenuwein T, Reinberg D, eds (2015) Epigenetics (Cold Spring Harbor Lab Press, New York), 2nd Ed.
  10. Gough DJ, Levy DE, Johnstone RW, Clarke CJ (2008) IFNgamma signaling-does it mean JAK-STAT? Cytokine Growth Factor Rev 19(5-6):383-394.
  11. Schindler C, Fu X-Y, Improta T, Aebersold R, Darnell JE, Jr (1992) Proteins of tran- scription factor ISGF-3: One gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci USA 89(16):7836-7839.
  12. Veals SA, et al. (1992) Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Mol Cell Biol 12(8):3315-3324.
  13. Horvath CM, Stark GR, Kerr IM, Darnell JE, Jr (1996) Interactions between STAT and non-STAT proteins in the interferon-stimulated gene factor 3 transcription complex. Mol Cell Biol 16(12):6957-6964.
  14. Zhang JJ, et al. (1996) Two contact regions between Stat1 and CBP/p300 in interferon gamma signaling. Proc Natl Acad Sci USA 93(26):15092-15096.
  15. Wojciak JM, Martinez-Yamout MA, Dyson HJ, Wright PE (2009) Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains. EMBO J 28(7):948-958.
  16. Lau JF, Nusinzon I, Burakov D, Freedman LP, Horvath CM (2003) Role of metazoan mediator proteins in interferon-responsive transcription. Mol Cell Biol 23(2):620-628.
  17. Zhang JJ, et al. (1998) Ser727-dependent recruitment of MCM5 by Stat1alpha in IFN- gamma-induced transcriptional activation. EMBO J 17(23):6963-6971.
  18. Zakharova N, et al. (2003) Distinct transcriptional activation functions of STAT1alpha and STAT1beta on DNA and chromatin templates. J Biol Chem 278(44):43067-43073.
  19. McMurray JS (2008) Structural basis for the binding of high affinity phosphopeptides to Stat3. Biopolymers 90(1):69-79.
  20. Yang E, Wen Z, Haspel RL, Zhang JJ, Darnell JE, Jr (1999) The linker domain of Stat1 is required for gamma interferon-driven transcription. Mol Cell Biol 19(7):5106-5112.
  21. Yang E, Henriksen MA, Schaefer O, Zakharova N, Darnell JE, Jr (2002) Dissociation time from DNA determines transcriptional function in a STAT1 linker mutant. J Biol Chem 277(16):13455-13462.
  22. Yang E (2002) Studies of transcriptional control by the STATs. Ph.D. thesis (The Rockefeller University, New York).
  23. Bromberg JF, et al. (1999) Stat3 as an oncogene. Cell 98(3):295-303.
  24. Li L, Shaw PE (2002) Autocrine-mediated activation of STAT3 correlates with cell proliferation in breast carcinoma lines. J Biol Chem 277(20):17397-17405.
  25. Casanova JL, Holland SM, Notarangelo LD (2012) Inborn errors of human JAKs and STATs. Immunity 36(4):515-528.
  26. Koskela HL, et al. (2012) Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 366(20):1905-1913.
  27. Jerez A, et al. (2013) STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients. Blood 122(14): 2453-2459.
  28. Flanagan SE, et al. (2014) Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet 46(8):812-814.
  29. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer 9(11):798-809.
  30. Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat Rev Cancer 14(11):736-746.
  31. Nakajima K, et al. (1996) A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J 15(14):3651-3658.
  32. Hart JR, Liao L, Yates JR, 3rd, Vogt PK (2011) Essential role of Stat3 in PI3K-induced oncogenic transformation. Proc Natl Acad Sci USA 108(32):13247-13252.
  33. ten Hoeve J, et al. (2002) Identification of a nuclear Stat1 protein tyrosine phos- phatase. Mol Cell Biol 22(16):5662-5668.
  34. Reich NC, Liu L (2006) Tracking STAT nuclear traffic. Nat Rev Immunol 6(8):602-612.
  35. Auzenne EJ, et al. (2012) A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis. J Exp Ther Oncol 10(2):155-162.
  36. Huang W, et al. (2014) A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and invasion. ACS Chem Biol 9(5):1188-1196.
  37. Siddiquee K, et al. (2007) Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA 104(18):7391-7396.
  38. Horvath CM, Wen Z, Darnell JE, Jr (1995) A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev 9(8):984-994.
  39. Li Y, et al. (2015) Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci USA 112(6):1839-1844.
  40. Yang J, et al. (2010) Reversible methylation of promoter-bound STAT3 by histone- modifying enzymes. Proc Natl Acad Sci USA 107(50):21499-21504.
  41. Ginsberg M, et al. (2007) Amino acid residues required for physical and cooperative transcriptional interaction of STAT3 and AP-1 proteins c-Jun and c-Fos. Mol Cell Biol 27(18):6300-6308.

Cited by

Sorted by citations

Authors
Mertens, C., Haripal, B., Klinge, S., & Darnell, J. E.
Affiliations
  • Rockefeller University (US)
  • Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10065-6399;
ORCID
Klinge, Sebastian
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-11-09
Volume
112
Issue
48
Pages
14811-14816
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1515876112
PMC
PMC4672786
OpenAlex
W2114775462
Cited by
59
References
3
Citations by year
2026: 4 · 2025: 6 · 2024: 10 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 10 · 2018: 2 · 2017: 4
FWCI
0.87
Type
journal article
Language
en
Update notices
correction (2015-12-22)
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 182 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Robertson Foundation (CEN5301029)
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 › Receptor Mechanisms and Signaling
Keywords
STAT3, linker domain, tyrosine phosphorylation, transcriptional activation, SH2 domain, DNA-binding domain, STAT1, protein dimerization, small molecule inhibitors, cancer
MeSH terms
Humans, Neoplasm Proteins, Neoplasms, Phosphorylation, Transcriptional Activation, Amino Acid Substitution, Mutation, Missense, Cell Line, Tumor, STAT1 Transcription Factor, STAT3 Transcription Factor, Protein Multimerization

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review