Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

G3BP1 promotes human breast cancer cell proliferation through coordinating with GSK-3β and stabilizing β-catenin

Abstract

Ras-GTPase activating SH3 domain-binding protein 1 (G3BP1) is a multifunctional binding protein involved in the development of a variety of human cancers. However, the role of G3BP1 in breast cancer progression remains largely unknown. In this study, we report that G3BP1 is upregulated and correlated with poor prognosis in breast cancer. Overexpression of G3BP1 promotes breast cancer cell proliferation by stimulating β-catenin signaling, which upregulates a number of proliferation-related genes. We further show that G3BP1 improves the stability of β-catenin by inhibiting its ubiquitin-proteasome degradation rather than affecting the transcription of β-catenin. Mechanistically, elevated G3BP1 interacts with and inactivates GSK-3β to suppress β-catenin phosphorylation and degradation. Disturbing the G3BP1-GSK-3β interaction accelerates the degradation of β-catenin, impairing the proliferative capacity of breast cancer cells. Our study demonstrates that the regulatory mechanism of the G3BP1/GSK-3β/β-catenin axis may be a potential therapeutic target for breast cancer.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Upregulated G3BP1 in breast cancer correlates with poor prognosis.
Fig. 2: G3BP1 promotes breast cancer cell proliferation.
Fig. 3: G3BP1 promotes breast cancer cell proliferation by regulating β-catenin signaling.
Fig. 4: G3BP1 inhibits the ubiquitination and degradation of β-catenin.
Fig. 5: G3BP1 interacts with GSK-3β and regulates its phosphorylation at S9 and Y216.
Fig. 6: GAP161 affects the interaction of G3BP1 and GSK-3β.

References

  1. 1.

    Yu QC, Verheyen EM, Zeng YA. Mammary development and breast cancer: a Wnt perspective. Cancers (Basel). 2016;8:65.

    Article  CAS  Google Scholar 

  2. 2.

    van Schie EH, van Amerongen R. Aberrant WNT/CTNNB1 signaling as a therapeutic target in human breast cancer: weighing the evidence. Front Cell Dev Biol. 2020;8:25.

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Yin P, Wang W, Zhang Z, Bai Y, Gao J, Zhao C. Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists. Cancer Sci. 2018;109:3368–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Kimelman D, Xu W. β-Catenin destruction complex: insights and questions from a structural perspective. Oncogene. 2006;25:7482–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of β-Catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837–47.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Liu C, Kato Y, Zhang Z, Do VM, Yankner BA, He X. β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation. Proc Natl Acad Sci USA. 1999;96:6273–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461–73.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–12.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Cadigan KM, Waterman ML. TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol. 2012;4:a007906.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Geyer FC, Lacroix-Triki M, Savage K, Arnedos M, Lambros MB, MacKay A, et al. β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod Pathol. 2011;24:209–31.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, Goss KH. Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol. 2010;176:2911–20.

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Karayiannakis AJ, Nakopoulou L, Gakiopoulou H, Keramopoulos A, Davaris PS, Pignatelli M. Expression patterns of β-catenin in in situ and invasive breast cancer. Eur J Surg Oncol. 2001;27:31–6.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Jang GB, Kim JY, Cho SD, Park KS, Jung JY, Lee HY, et al. Blockade of Wnt/β-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Sci Rep. 2015;5:12465.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Li K, Zhang J, Tian Y, He Y, Xu X, Pan W, et al. The Wnt/β-catenin/VASP positive feedback loop drives cell proliferation and migration in breast cancer. Oncogene. 2020;39:2258–74.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Laver JD, Ly J, Winn AK, Karaiskakis A, Lin S, Nie K, et al. The RNA-binding protein Rasputin/G3BP enhances the stability and translation of its target mRNAs. Cell Rep. 2020;30:3353–67.e7.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Yang P, Mathieu C, Kolaitis R-M, Zhang P, Messing J, Yurtsever U, et al. G3BP1 is a tunable switch that triggers phase separation to assemble stress granules. Cell. 2020;181:325–45.e28.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Yang W, Ru Y, Ren J, Bai J, Wei J, Fu S, et al. G3BP1 inhibits RNA virus replication by positively regulating RIG-I-mediated cellular antiviral response. Cell Death Dis. 2019;10:946.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Liu ZS, Cai H, Xue W, Wang M, Xia T, Li WJ, et al. G3BP1 promotes DNA binding and activation of cGAS. Nat Immunol. 2019;20:18–28.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Wang Y, Su J, Wang Y, Fu D, Ideozu JE, Geng H, et al. The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1-SPP1- NF-κB signaling axis. J Exp Clin Cancer Res. 2019;38:386.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Alam U, Kennedy D. Rasputin a decade on and more promiscuous than ever? A review of G3BPs. Biochim Biophys Acta Mol Cell Res. 2019;1866:360–70.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Wang Y, Fu D, Chen Y, Su J, Wang Y, Li X, et al. G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas. Cell Death Dis. 2018;9:501.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Xiong R, Gao JL, Yin T. G3BP1 activates the TGF-β/Smad signaling pathway to promote gastric cancer. Onco Targets Ther. 2019;12:7149–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Zhang LN, Zhao L, Yan XL, Huang YH. Loss of G3BP1 suppresses proliferation, migration, and invasion of esophageal cancer cells via Wnt/β-catenin and PI3K/AKT signaling pathways. J Cell Physiol. 2019;234:20469–84.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Zhang H, Ma Y, Zhang S, Liu H, He H, Li N, et al. Involvement of Ras GTPase-activating protein SH3 domain-binding protein 1 in the epithelial-to-mesenchymal transition-induced metastasis of breast cancer cells via the Smad signaling pathway. Oncotarget. 2015;6:17039–53.

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Zhang H, Zhang SH, He HW, Zhang CX, Yu DK, Shao RG. Downregulation of G3BPs inhibits the growth, migration and invasion of human lung carcinoma H1299 cells by suppressing the Src/FAK-associated signaling pathway. Cancer Gene Ther. 2013;20:622–9.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Ma X-J, Dahiya S, Richardson E, Erlander M, Sgroi DC. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res. 2009;11:R7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100:8418–23.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Glück S, Ross JS, Royce M, McKenna EF, Perou CM, Avisar E, et al. TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine ± trastuzumab. Breast Cancer Res Treat. 2012;132:781–91.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  31. 31.

    Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell. 2006;9:121–32.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.

    Article  Google Scholar 

  33. 33.

    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation By phosphorylation. Mol Cell. 2001;7:1321–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Ma C, Wang J, Gao Y, Gao TW, Chen G, Bower KA, et al. The role of glycogen synthase kinase 3β in the transformation of epidermal cells. Cancer Res. 2007;67:7756.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Stamos JL, Weis WI. The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5:a007898-a.

    Article  CAS  Google Scholar 

  37. 37.

    Zhang H, Zhang S, He H, Zhao W, Chen J, Shao RG. GAP161 targets and downregulates G3BP to suppress cell growth and potentiate cisplaitin-mediated cytotoxicity to colon carcinoma HCT116 cells. Cancer Sci. 2012;103:1848–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Zheng H, Zhan Y, Zhang Y, Liu S, Lu J, Yang Y, et al. Elevated expression of G3BP1 associates with YB1 and p-AKT and predicts poor prognosis in nonsmall cell lung cancer patients after surgical resection. Cancer Med. 2019;8:6894–903.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Min L, Ruan Y, Shen Z, Jia D, Wang X, Zhao J, et al. Overexpression of Ras-GTPase-activating protein SH3 domain-binding protein 1 correlates with poor prognosis in gastric cancer patients. Histopathology. 2015;67:677–88.

    PubMed  Article  Google Scholar 

  40. 40.

    Guitard E, Parker F, Millon R, Abecassis J, Tocqué B. G3BP is overexpressed in human tumors and promotes S phase entry. Cancer Lett. 2001;162:213–21.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Winslow S, Leandersson K, Larsson C. Regulation of PMP22 mRNA by G3BP1 affects cell proliferation in breast cancer cells. Mol Cancer. 2013;12:156.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, et al. FoxM1 promotes β-catenin nuclear localization and controls wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011;20:427–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Wu X, Tu X, Joeng KS, Hilton MJ, Williams DA, Long F. Rac1 activation controls nuclear localization of β-catenin during canonical Wnt signaling. Cell. 2008;133:340–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Fagotto F, Glück U, Gumbiner BM. Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of β-catenin. Curr Biol. 1998;8:181–90.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Bikkavilli RK, Malbon CC. Arginine methylation of G3BP1 in response to Wnt3a regulates β-catenin mRNA. J Cell Sci. 2011;124:2310-20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Säfholm A, Tuomela J, Rosenkvist J, Dejmek J, Härkönen P, Andersson T. The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility. Clin Cancer Res. 2008;14:6556-63.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Ettenberg SA, Charlat O, Daley MP, Liu S, Vincent KJ, Stuart DD, et al. Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies. Proc Natl Acad Sci USA. 2010;107:15473.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Lee JH, Faderl S, Pagel JM, Jung CW, Yoon SS, Pardanani AD, et al. Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. Blood Adv. 2020;4:2032–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Gandhirajan RK, Staib PA, Minke K, Gehrke I, Plickert G, Schlösser A, et al. Small molecule inhibitors of Wnt/β-catenin/Lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. Neoplasia. 2010;12:326–IN6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Jang GB, Hong IS, Kim RJ, Lee SY, Park SJ, Lee ES, et al. Wnt/β-Catenin small-molecule inhibitor CWP232228 preferentially inhibits the growth of breast cancer stem-like cells. Cancer Res. 2015;75:1691–702.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Kennedy D, French J, Guitard E, Ru K, Tocque B, Mattick J. Characterization of G3BPs: tissue specific expression, chromosomal localisation and rasGAP120 binding studies. J Cell Biochem. 2002;84:173–87.

    Article  Google Scholar 

  52. 52.

    Nagai K, Oubridge C, Ito N, Avis J, Evans P. The RNP domain: a sequence-specific RNA-binding domain involved in processing and transport of RNA. Trends Biochem Sci. 1995;20:235–40.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Cross DAE, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785–9.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 1993;12:803–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Cheng PW, Chen YY, Cheng WH, Lu PJ, Chen HH, Chen BR, et al. Wnt signaling regulates blood pressure by downregulating a GSK-3β–mediated pathway to enhance insulin signaling in the central nervous system. Diabetes. 2015;64:3413.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Wang XY, Zhang XZ, Li F, Ji QR. MiR-128-3p accelerates cardiovascular calcification and insulin resistance through ISL1-dependent Wnt pathway in type 2 diabetes mellitus rats. J Cell Physiol. 2019;234:4997–5010.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Li J, Mizukami Y, Zhang X, Jo WS, Chung DC. Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3β. Gastroenterology. 2005;128:1907–18.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We thank Dr. Xue-min Zhang and Tao Li (National Center of Biomedical Analysis, Beijing, China) for gifting the G3BP1 truncation mutant plasmids. This work was supported by the National Key Research and Development Program of China (2016YFA0201504), National Natural Science Foundation of China (No. 81673471, 81102464), the CAMS Initiative for Innovative Medicine (2016-I2M-2-002), and the Drug Innovation Major Project of China (2018ZX09711001-007-002).

Author information

Affiliations

Authors

Contributions

RGS: conceptualization, writing-reviewing, and editing, funding acquisition. CHZ: data curation, validation, formal analysis, writing-original draft preparation, and visualization. HL and WLZ: methodology. WXZ and HMZ: Investigation.

Corresponding author

Correspondence to Rong-guang Shao.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, Ch., Liu, H., Zhao, Wl. et al. G3BP1 promotes human breast cancer cell proliferation through coordinating with GSK-3β and stabilizing β-catenin. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-020-00598-w

Download citation

Keywords

  • G3BP1
  • Wnt/β-catenin signaling pathway
  • GSK-3β phosphorylation
  • protein stability
  • breast cancer
  • peptide antagonist

Search

Quick links