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SGT1 regulates Akt signaling by promoting beta-TrCP-dependent PHLPP1 degradation in gastric cancer cells

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Abstract

SGT1 (suppressor of G2 allele of Skp1) plays a role in various cellular processes including kinetochore assembly and protein ubiquitination by interacting with Skp1, a component of SCF E3 ligase complex. However, the function of SGT1 in cancer is largely unknown. Here, we showed that SGT1 was over-expressed in gastric cancer tissues and silencing of SGT1 by siRNAs significantly inhibited the growth and colony formation of gastric cancer cells. We further showed that SGT1 could regulate Akt signaling pathway by modulating Akt ser473 phosphorylation status. Moreover, we found that SGT1 was able to regulate the stability of PHLPP1, which is the direct phosphatase for Akt ser473 phosphorylation. Immunoprecipitation assay revealed that SGT1 could enhance the binding between PHLPP1 and beta-TrCP which has been documented to be able to target PHLPP1 for destruction. Decreased PHLPP1 in SGT1 over-expressed gastric cancer cells failed to dephosphorylate Akt and resulted in increased Akt ser473 phosphorylation and amplified downstream Akt signaling. Thus, our data revealed a previously uncovered role of SGT1 in gastric cancer development, and suggested that SGT1 could be a promising anti-cancer target to against gastric cancer.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86

    Article  PubMed  CAS  Google Scholar 

  3. Michl P, Downward J (2005) Mechanisms of disease: PI3K/AKT signaling in gastrointestinal cancers. Z Gastroenterol 43:1133–1139

    Article  PubMed  CAS  Google Scholar 

  4. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    Article  PubMed  CAS  Google Scholar 

  5. Qiao M, Sheng S, Pardee AB (2008) Metastasis and AKT activation. Cell Cycle 7:2991–2996

    Article  PubMed  CAS  Google Scholar 

  6. Georgescu MM (2010) PTEN tumor suppressor network in PI3 K-Akt pathway control. Genes Cancer 1:1170–1177

    Article  PubMed  CAS  Google Scholar 

  7. Li J, Yen C, Liaw D, Podsypanina K, Bose S et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947

    Article  PubMed  CAS  Google Scholar 

  8. Lazar D, Raica M, Sporea I, Taban S, Goldis A et al (2006) Tumor angiogenesis in gastric cancer. Rom J Morphol Embryol 47:5–13

    PubMed  Google Scholar 

  9. Almhanna K, Strosberg J, Malafa M (2011) Targeting AKT protein kinase in gastric cancer. Anticancer Res 31:4387–4392

    PubMed  CAS  Google Scholar 

  10. Gao T, Furnari F, Newton AC (2005) PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 18:13–24

    Article  PubMed  CAS  Google Scholar 

  11. Brognard J, Sierecki E, Gao T, Newton AC (2007) PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 25:917–931

    Article  PubMed  CAS  Google Scholar 

  12. Qiao M, Iglehart JD, Pardee AB (2007) Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation. Cancer Res 67:5293–5299

    Article  PubMed  CAS  Google Scholar 

  13. Li X, Liu J, Gao T (2009) beta-TrCP-mediated ubiquitination and degradation of PHLPP1 are negatively regulated by Akt. Mol Cell Biol 29:6192–6205

    Article  PubMed  CAS  Google Scholar 

  14. Kitagawa K, Skowyra D, Elledge SJ, Harper JW, Hieter P (1999) SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. Mol Cell 4:21–33

    Article  PubMed  CAS  Google Scholar 

  15. Mayor A, Martinon F, De Smedt T, Petrilli V, Tschopp J (2007) A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat Immunol 8:497–503

    Article  PubMed  CAS  Google Scholar 

  16. Kadota Y, Shirasu K, Guerois R (2010) NLR sensors meet at the SGT1-HSP90 crossroad. Trends Biochem Sci 35:199–207

    Article  PubMed  CAS  Google Scholar 

  17. Shirasu K (2009) The HSP90-SGT1 chaperone complex for NLR immune sensors. Annu Rev Plant Biol 60:139–164

    Article  PubMed  CAS  Google Scholar 

  18. Iwatsuki M, Mimori K, Sato T, Toh H, Yokobori T et al (2010) Overexpression of SUGT1 in human colorectal cancer and its clinicopathological significance. Int J Oncol 36:569–575

    PubMed  CAS  Google Scholar 

  19. Mendoza MC, Blenis J (2007) PHLPPing it off: phosphatases get in the Akt. Mol Cell 25:798–800

    Article  PubMed  CAS  Google Scholar 

  20. Molina JR, Agarwal NK, Morales FC, Hayashi Y, Aldape KD et al (2011) PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma. Oncogene 31(10):1264–1274

    Article  PubMed  Google Scholar 

  21. Chen M, Pratt CP, Zeeman ME, Schultz N, Taylor BS et al (2011) Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression. Cancer Cell 20:173–186

    Article  PubMed  CAS  Google Scholar 

  22. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y et al (2011) Reciprocal feedback regulation of PI3 K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19:575–586

    Article  PubMed  CAS  Google Scholar 

  23. Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L et al (2003) Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Dev Cell 4:799–812

    Article  PubMed  CAS  Google Scholar 

  24. Peschiaroli A, Dorrello NV, Guardavaccaro D, Venere M, Halazonetis T et al (2006) SCFbetaTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. Mol Cell 23:319–329

    Article  PubMed  CAS  Google Scholar 

  25. Ougolkov A, Zhang B, Yamashita K, Bilim V, Mai M et al (2004) Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer. J Natl Cancer Inst 96:1161–1170

    Article  PubMed  CAS  Google Scholar 

  26. Frescas D, Pagano M (2008) Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 8:438–449

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the anonymous reviewer for the suggestions that help to improve the work.

Conflict of interest

None of the authors has any potential conflicts of interest.

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Authors and Affiliations

  1. Department of General Surgery, Central Hospital of Fengxian District, Shanghai, China

    Ganglong Gao, Min Qian, Zhenfeng Yu, Haiqin Zhang, Qiang Zhang, Jianping Gu & Xueli Zhang

  2. Department of Pathology, Changning Central Hospital, Shanghai, China

    Tao Kun

  3. Department of Pathology, Central Hospital of Fengxian District, Shanghai, China

    Youhua Sheng

  4. Department of General Surgery, College of Medicine, Soochow University, Suzhou, China

    Fanzhi Kong

  5. Department of Surgery, Longsai Hospital, Ningbo, Zhejiang, China

    Xiaoguang Liu

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  1. Ganglong Gao
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  2. Tao Kun
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  3. Youhua Sheng
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  4. Min Qian
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  5. Fanzhi Kong
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  6. Xiaoguang Liu
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  7. Zhenfeng Yu
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  8. Haiqin Zhang
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  9. Qiang Zhang
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  10. Jianping Gu
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  11. Xueli Zhang
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Corresponding authors

Correspondence to Jianping Gu or Xueli Zhang.

Additional information

Ganglong Gao and Kun Tao contributed equally to this study

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Gao, G., Kun, T., Sheng, Y. et al. SGT1 regulates Akt signaling by promoting beta-TrCP-dependent PHLPP1 degradation in gastric cancer cells. Mol Biol Rep 40, 2947–2953 (2013). https://doi.org/10.1007/s11033-012-2363-8

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  • DOI: https://doi.org/10.1007/s11033-012-2363-8

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