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.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Yu QC, Verheyen EM, Zeng YA. Mammary development and breast cancer: a Wnt perspective. Cancers (Basel). 2016;8:65.
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.
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.
Kimelman D, Xu W. β-Catenin destruction complex: insights and questions from a structural perspective. Oncogene. 2006;25:7482–91.
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.
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.
Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461–73.
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.
Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.
Cadigan KM, Waterman ML. TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol. 2012;4:a007906.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.
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.
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.
Stamos JL, Weis WI. The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5:a007898-a.
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.
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.
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.
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.
Winslow S, Leandersson K, Larsson C. Regulation of PMP22 mRNA by G3BP1 affects cell proliferation in breast cancer cells. Mol Cancer. 2013;12:156.
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.
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.
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.
Bikkavilli RK, Malbon CC. Arginine methylation of G3BP1 in response to Wnt3a regulates β-catenin mRNA. J Cell Sci. 2011;124:2310-20.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
Conflict of interest
The authors declare no competing interests.
About this article
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
- Wnt/β-catenin signaling pathway
- GSK-3β phosphorylation
- protein stability
- breast cancer
- peptide antagonist