Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains.

Szczegóły
Abstrakt

Tytuł:: Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains.
Autorzy:: La Sala G; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Station 19, 1015, Lausanne, Switzerland.
Michiels C; Experimental Medicine Unit, De Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
Kükenshöner T; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Station 19, 1015, Lausanne, Switzerland.
Brandstoetter T; Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
Maurer B; Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
Koide A; Department of Medicine, New York University School of Medicine, 522 1st Avenue, New York, 10016, NY, USA.; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, 522 1st Avenue, New York, 10016, NY, USA.
Lau K; Protein Crystallography Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne, Station 19, 1015, Lausanne, Switzerland.
Pojer F; Protein Crystallography Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne, Station 19, 1015, Lausanne, Switzerland.
Koide S; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, 522 1st Avenue, New York, 10016, NY, USA.; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 1st Avenue, New York, 10016, NY, USA.
Sexl V; Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
Dumoutier L; Experimental Medicine Unit, De Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
Hantschel O; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Station 19, 1015, Lausanne, Switzerland. .; Faculty of Medicine, Institute of Physiological Chemistry, Philipps-University of Marburg, Karl-von-Frisch-Straße 1, 35032, Marburg, Germany. .
Źródło:: Nature communications [Nat Commun] 2020 Aug 17; Vol. 11 (1), pp. 4115. Date of Electronic Publication: 2020 Aug 17.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Antibodies/*metabolism
STAT3 Transcription Factor/*metabolism
A549 Cells ; Antibodies/genetics ; Blotting, Western ; Calorimetry ; Crystallography, X-Ray ; Flow Cytometry ; Fluorescence Polarization ; Fluorescent Antibody Technique ; Humans ; Mass Spectrometry ; Protein Binding ; Protein Domains/immunology ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/immunology ; Signal Transduction/genetics ; Signal Transduction/physiology ; Synthetic Biology
References:: Loh, C.-Y. et al. Signal Transducer and Activator of Transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication. Front. Oncol. 9, 48 (2019). (PMID: 30847297639334810.3389/fonc.2019.00048)
Schindler, C., Levy, D. E. & Decker, T. JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 282, 20059–20063 (2007). (PMID: 1750236710.1074/jbc.R700016200)
Johnson, D., O’Keefe, R. & Grandis, J. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234–248 (2018). (PMID: 29405201585897110.1038/nrclinonc.2018.8)
Haura, E. B., Turkson, J. & Jove, R. Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat. Clin. Pract. Oncol. 2, 315–324 (2005). (PMID: 1626498910.1038/ncponc0195)
Reich, N. C. STATs get their move on. JAKSTAT 2, e27080 (2013). (PMID: 244709783891633)
Miranda, C. et al. Role of STAT3 in in vitro transformation triggered by TRK oncogenes. PLoS ONE 5, e9446 (2010). (PMID: 20209132283105910.1371/journal.pone.0009446)
Yuan, J., Zhang, F. & Niu, R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci. Rep. 5, 17663 (2015). (PMID: 26631279466839210.1038/srep17663)
O’Shea, J. J., Kanno, Y., Chen, X. & Levy, D. E. Stat acetylation–a key facet of cytokine signaling? Science 307, 217–218 (2005). (PMID: 1565349310.1126/science.1108164)
Zhao, C. et al. Feedback activation of STAT3 as a cancer drug-resistance mechanism. Trends Pharmacol. Sci. 37, 47–61 (2016). (PMID: 2657683010.1016/j.tips.2015.10.001)
Bollrath, J. et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15, 91–102 (2009). (PMID: 1918584410.1016/j.ccr.2009.01.002)
Bromberg, J. F., Horvath, C. M., Besser, D., Lathem, W. W. & Darnell, J. E. Stat3 activation is required for cellular transformation by v-src. Mol. Cell. Bio. 18, 2553–2558 (1998). (PMID: 10.1128/MCB.18.5.2553)
Banerjee, K. & Resat, H. Constitutive activation of STAT3 in breast cancer cells: a review. Int. J. Cancer 138, 2570–2578 (2016). (PMID: 2655937310.1002/ijc.29923)
Wingelhofer, B. et al. Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia 32, 1713–1726 (2018). (PMID: 29728695608771510.1038/s41375-018-0117-x)
Yu, H. & Jove, R. The STATs of cancer—new molecular targets come of age. Nat. Rev. Cancer 4, 97–105 (2004). (PMID: 1496430710.1038/nrc1275)
Yu, H., Lee, H., Herrmann, A., Buettner, R. & Jove, R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat. Rev. Cancer 14, 736–746 (2014). (PMID: 2534263110.1038/nrc3818)
Koskela, H. et al. Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia. N. Engl. J. Med. 366, 1905–1913 (2012). (PMID: 22591296369386010.1056/NEJMoa1114885)
Barilà, G. et al. Stat3 mutations impact on overall survival in large granular lymphocyte leukemia: a single-center experience of 205 patients. Leukemia 34, 1116–1124 (2019). (PMID: 3174081010.1038/s41375-019-0644-0)
Huynh, J., Chand, A., Gough, D. & Ernst, M. Therapeutically exploiting STAT3 activity in cancer—using tissue repair as a road map. Nat. Rev. Cancer 19, 1 (2018).
Orlova, A. et al. Direct targeting options for STAT3 and STAT5 in cancer. Cancers 11, 1930 (2019). (PMID: 696657010.3390/cancers11121930)
Sgrignani, J. et al. Structural biology of STAT3 and its implications for anticancer therapies development. Int. J. Mol. Sci. 19, 1591 (2018). (PMID: 603220810.3390/ijms19061591)
Becker, S., Groner, B. & Müller, C. W. Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature 394, 145–151 (1998). (PMID: 967129810.1038/28101)
Vogt, M. et al. The role of the N-terminal domain in dimerization and nucleocytoplasmic shuttling of latent STAT3. J. Cell Sci. 124, 900–909 (2011). (PMID: 2132502610.1242/jcs.072520)
Hu, T. et al. Impact of the N-terminal domain of STAT3 in STAT3-dependent transcriptional activity. Mol. Cell. Biol. 35, 3284–3300 (2015). (PMID: 26169829456172810.1128/MCB.00060-15)
Ma, J. & Cao, X. Regulation of Stat3 nuclear import by importin α5 and importin α7 via two different functional sequence elements. Cell. Sign. 18, 1117–1126 (2006). (PMID: 10.1016/j.cellsig.2005.06.016)
Sato, N. et al. Nuclear retention of STAT3 through the coiled-coil domain regulates its activity. Biochem. Biophys. Res. Commun. 336, 617–624 (2005). (PMID: 1614026810.1016/j.bbrc.2005.08.145)
Ma, J., Zhang, T., Novotny-Diermayr, V., Tan, A. L. & Cao, X. A novel sequence in the coiled-coil domain of Stat3 essential for its nuclear translocation. J. Biol. Chem. 278, 29252–29260 (2003). (PMID: 1274644110.1074/jbc.M304196200)
Dumoutier, L., Meester, C., de, Tavernier, J. & Renauld, J.-C. New activation modus of STAT3: a tyrosine-less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain. J. Biol. Chem. 284, 26377–26384 (2009). (PMID: 19632985278532510.1074/jbc.M109.007955)
Markota, A., Endres, S. & Kobold, S. Targeting interleukin-22 for cancer therapy. Hum. Vacc. Immunother. 14, 2012–2015 (2018). (PMID: 10.1080/21645515.2018.1461300)
Koide, A., Bailey, C. W., Huang, X. & Koide, S. The fibronectin type III domain as a scaffold for novel binding proteins. Mol. Biol. 284, 1141–1151 (1998).
Koide, A. & Koide, S. Monobodies: antibody mimics based on the scaffold of the fibronectin type III domain. Meth. Mol. Biol. 352, 95–109 (2007).
Koide, A., Wojcik, J., Gilbreth, R. N., Hoey, R. J. & Koide, S. Teaching an old scaffold new tricks: monobodies constructed using alternative surfaces of the FN3 scaffold. J. Mol. Biol. 415, 393–405 (2012). (PMID: 2219840810.1016/j.jmb.2011.12.019)
Verdine, G. L. & Walensky, L. D. The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin. Can. Res. 13, 7264–7270 (2007). (PMID: 10.1158/1078-0432.CCR-07-2184)
Wojcik, J. et al. Allosteric inhibition of Bcr-Abl kinase by high affinity monobody inhibitors directed to the Src Homology 2 (SH2)-kinase interface. J. Biol. Chem. 291, 8836–8847 (2016). (PMID: 2691265910.1074/jbc.M115.707901)
Grebien, F. et al. Targeting the SH2-Kinase interface in Bcr-Abl Inhibits Leukemogenesis. Cell 147, 306–319 (2011). (PMID: 22000011320266910.1016/j.cell.2011.08.046)
Kükenshöner, T. et al. Selective targeting of SH2 domain–phosphotyrosine interactions of src family tyrosine kinases with monobodies. J. Mol. Biol. 429, 1364–1380 (2017). (PMID: 28347651541732310.1016/j.jmb.2017.03.023)
Zorba, A. et al. Allosteric modulation of a human protein kinase with monobodies. Proc. Natl Acad. Sci. USA 116, 13937–13942 (2019). (PMID: 3123934210.1073/pnas.19060241166628680)
Sha, F. et al. Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains. Proc. Natl Acad. Sci. USA 110, 14924–14929 (2013). (PMID: 2398015110.1073/pnas.13036401103773763)
Spencer-Smith, R. et al. Inhibition of RAS function through targeting an allosteric regulatory site. Nat. Chem. Biol. 13, 62–68 (2016). (PMID: 27820802519336910.1038/nchembio.2231)
Sha, F., Salzman, G., Gupta, A. & Koide, S. Monobodies and other synthetic binding proteins for expanding protein science. Protein Sci. 26, 910–924 (2017). (PMID: 28249355540542410.1002/pro.3148)
Hantschel, O., Biancalana, M. & Koide, S. Monobodies as enabling tools for structural and mechanistic biology. Curr. Opin. Struc. Biol. 60, 167–174 (2020). (PMID: 10.1016/j.sbi.2020.01.015)
Pencik, J. et al. JAK-STAT signaling in cancer: from cytokines to non-coding genome. Cytokine 87, 26–36 (2016). (PMID: 27349799605936210.1016/j.cyto.2016.06.017)
Schmit, N., Neopane, K. & Hantschel, O. Targeted protein degradation through cytosolic delivery of monobody binders using bacterial toxins. ACS Chem. Biol. 14, 916–924 (2019). (PMID: 31025848731656910.1021/acschembio.9b00113)
Fulcher, L. J., Hutchinson, L. D., Macartney, T. J., Turnbull, C. & Sapkota, G. P. Targeting endogenous proteins for degradation through the affinity-directed protein missile system. Open Biol. 7, 170066 (2017). (PMID: 28490657545154610.1098/rsob.170066)
Wojcik, J. et al. A potent and highly specific FN3 monobody inhibitor of the Abl SH2 domain. Nat. Struct. Mol. Biol. 17, 519–527 (2010). (PMID: 20357770292694010.1038/nsmb.1793)
Nelson, E. A. et al. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood 112, 5095–5102 (2008). (PMID: 18824601259760710.1182/blood-2007-12-129718)
Drake, C. et al. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol. 179, 4313–4317 (2007). (PMID: 1787832510.4049/jimmunol.179.7.4313)
Majoros, A. et al. Canonical and non-canonical aspects of JAK–STAT signaling: lessons from interferons for cytokine responses. Front. Immunol. 8, 29 (2017). (PMID: 28184222526672110.3389/fimmu.2017.00029)
Johnston, P. A. & Grandis, J. R. STAT3 signaling: anticancer strategies and challenges. Mol. Interv. 11, 18–26 (2011). (PMID: 21441118306371610.1124/mi.11.1.4)
Lee, T. I. & Young, R. A. Transcriptional regulation and its misregulation in disease. Cell 152, 1237–1251 (2013). (PMID: 23498934364049410.1016/j.cell.2013.02.014)
Makley, L. N. & Gestwicki, J. E. Expanding the number of ‘Druggable’ targets: non‐enzymes and protein–protein interactions. Chem. Biol. Drug Des. 81, 22–32 (2013). (PMID: 23253128353188010.1111/cbdd.12066)
Yue, P. & Turkson, J. Targeting STAT3 in cancer: how successful are we? Expert Opin. Investig. Drugs 18, 45–56 (2008). (PMID: 10.1517/13543780802565791)
Jing, N. & Tweardy, D. J. Targeting Stat3 in cancer therapy. Anticancer Drugs 16, 601 (2005). (PMID: 1593088610.1097/00001813-200507000-00002)
Hinde, E. et al. Quantifying the dynamics of the oligomeric transcription factor STAT3 by pair correlation of molecular brightness. Nat. Commun. 7, 1–14 (2016). (PMID: 10.1038/ncomms11047)
Primiano, T. et al. Identification of potential anticancer drug targets through the selection of growth-inhibitory genetic suppressor elements. Cancer Cell 4, 41–53 (2003). (PMID: 1289271210.1016/S1535-6108(03)00169-7)
Duan, J., Wu, J., Valencia, A., er, C. & Liu, R. Fibronectin type III domain based monobody with high avidity. Biochem.-us 46, 12656–12664 (2007). (PMID: 10.1021/bi701215e)
Kabsch, W. Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants. J. Appl Crystallogr 26, 795–800 (1993). (PMID: 10.1107/S0021889893005588)
Vagin, A. A. et al. REFMAC 5 dictionary: organization of prior chemical knowledge and guidelines for its use. Acta Crystallogr. Sect. D. Biol. Crystallogr. 60, 2184–2195 (2004). (PMID: 10.1107/S0907444904023510)
Bürckstümmer, T. et al. An efficient tandem affinity purification procedure for interaction proteomics in mammalian cells. Nat. Methods 3, 1013–1019 (2006). (PMID: 1706090810.1038/nmeth968)
Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007). (PMID: 1770320110.1038/nprot.2007.261)
Reckel, S. et al. Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase. Nat. Commun. 8, 2101 (2017). (PMID: 29235475572738610.1038/s41467-017-02313-6)
Perez-Riverol, Y. et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 47, D442–D450 (2018). (PMID: 632389610.1093/nar/gky1106)
Lynch, R. A., Etchin, J., Battle, T. E. & Frank, D. A. A small-molecule enhancer of signal transducer and activator of transcription 1 transcriptional activity accentuates the antiproliferative effects of IFN-γ in human cancer cells. Cancer Res. 67, 1254–1261 (2007). (PMID: 1728316210.1158/0008-5472.CAN-06-2439)
Grant Information:: U01 MH109102 United States MH NIMH NIH HHS; R01 CA194864 United States CA NCI NIH HHS
Substance Nomenclature:: 0 (Antibodies)
0 (STAT3 Transcription Factor)
0 (STAT3 protein, human)
Entry Date(s):: Date Created: 20200819 Date Completed: 20200908 Latest Revision: 20220422
Update Code:: 20240104
PubMed Central ID:: PMC7431413
DOI:: 10.1038/s41467-020-17920-z
PMID:: 32807795
: Czasopismo naukowe

Full Text Finder

The transcription factor STAT3 is frequently activated in human solid and hematological malignancies and remains a challenging therapeutic target with no approved drugs to date. Here, we develop synthetic antibody mimetics, termed monobodies, to interfere with STAT3 signaling. These monobodies are highly selective for STAT3 and bind with nanomolar affinity to the N-terminal and coiled-coil domains. Interactome analysis detects no significant binding to other STATs or additional off-target proteins, confirming their exquisite specificity. Intracellular expression of monobodies fused to VHL, an E3 ubiquitin ligase substrate receptor, results in degradation of endogenous STAT3. The crystal structure of STAT3 in complex with monobody MS3-6 reveals bending of the coiled-coil domain, resulting in diminished DNA binding and nuclear translocation. MS3-6 expression strongly inhibits STAT3-dependent transcriptional activation and disrupts STAT3 interaction with the IL-22 receptor. Therefore, our study establishes innovative tools to interfere with STAT3 signaling by different molecular mechanisms.

Informacja