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.

  • Article
  • Published:

Signal peptide peptidase promotes tumor progression via facilitating FKBP8 degradation

Oncogene volume 38, pages 1688–1701 (2019)Cite this article

Subjects

Abstract

Signal peptide peptidase (SPP) is an endoplasmic reticulum (ER)-resident aspartyl protease mediating intramembrane cleavage of type II transmembrane proteins. Increasing evidence has supported the role of SPP in ER-associated protein degradation. In the present study, we show that SPP expression is highly induced in human lung and breast cancers and correlated with disease outcome. Stable depletion of SPP expression in lung and breast cancer cell lines significantly reduced cell growth and migration/invasion abilities. Quantitative analysis of the proteomic changes of microsomal proteins in lung cancer cells by the stable isotope labeling with amino acids in cell culture (SILAC) approach revealed that the level of FKBP8, an endogenous inhibitor of mTOR, was significantly increased following SPP depletion. Co-immunoprecipitation assay and confocal immunofluorescence demonstrated that SPP interacted and colocalized with FKBP8 in ER, supporting that FKBP8 is a protein substrate of SPP. Cycloheximide chase and proteasome inhibition experiments revealed that SPP-mediated proteolysis facilitated FKBP8 protein degradation in cytosol. Further experiment demonstrated that the levels of phosphorylation in mTOR and its downstream effectors, S6K and 4E-BP1, were significantly lower in SPP-depleted cells. The reduced mTOR signaling and decreases of growth and migration/invasion abilities induced by SPP depletion in cancer cells could be reversed by FKBP8 downregulation. The implication of FKBP8 in SPP-mediated tumorigenicity was also observed in the xenograft model. Together, these findings disclose that SPP promotes tumor progression, at least in part, via facilitating the degradation of FKBP8 to enhance mTOR signaling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Brown MS, Ye J, Rawson RB, Goldstein JL. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell. 2000;100:391–8.

    Article  CAS  Google Scholar 

  2. Urban S, Freeman M. Intramembrane proteolysis controls diverse signalling pathways throughout evolution. Curr Opin Genet Dev. 2002;12:512–8.

    Article  CAS  Google Scholar 

  3. Wolfe MS. Intramembrane-cleaving proteases. J Biol Chem. 2009;284:13969–73.

    Article  CAS  Google Scholar 

  4. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science. 2002;296:2215–8.

    Article  CAS  Google Scholar 

  5. Voss M, Schroder B, Fluhrer R. Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases. Biochim Biophys Acta. 2013;1828:2828–39.

    Article  CAS  Google Scholar 

  6. Lemberg MK, Martoglio B. Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Mol Cell. 2002;10:735–44.

    Article  CAS  Google Scholar 

  7. Okamoto K, Moriishi K, Miyamura T, Matsuura Y. Intramembrane proteolysis and endoplasmic reticulum retention of hepatitis C virus core protein. J Virol. 2004;78:6370–80.

    Article  CAS  Google Scholar 

  8. Targett-Adams P, Schaller T, Hope G, Lanford RE, Lemon SM, Martin A, et al. Signal peptide peptidase cleavage of GB virus B core protein is required for productive infection in vivo. J Biol Chem. 2006;281:29221–7.

    Article  CAS  Google Scholar 

  9. Shi X, Botting CH, Li P, Niglas M, Brennan B, Shirran SL, et al. Bunyamwera orthobunyavirus glycoprotein precursor is processed by cellular signal peptidase and signal peptide peptidase. Proc Natl Acad Sci USA. 2016;113:8825–30.

    Article  CAS  Google Scholar 

  10. Avci D, Lemberg MK. Clipping or extracting: two ways to membrane protein degradation. Trends Cell Biol. 2015;25:611–22.

    Article  CAS  Google Scholar 

  11. Mentrup T, Fluhrer R, Schroder B. Latest emerging functions of SPP/SPPL intramembrane proteases. Eur J Cell Biol. 2017;96:372–82.

    Article  CAS  Google Scholar 

  12. Loureiro J, Lilley BN, Spooner E, Noriega V, Tortorella D, Ploegh HL. Signal peptide peptidase is required for dislocation from the endoplasmic reticulum. Nature. 2006;441:894–7.

    Article  CAS  Google Scholar 

  13. Hsu FF, Yeh CT, Sun YJ, Chiang MT, Lan WM, Li FA, et al. Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity. Oncogene. 2015;34:2360–70.

    Article  CAS  Google Scholar 

  14. Boname JM, Bloor S, Wandel MP, Nathan JA, Antrobus R, Dingwell KS, et al. Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins. J Cell Biol. 2014;205:847–62.

    Article  CAS  Google Scholar 

  15. Chen CY, Malchus NS, Hehn B, Stelzer W, Avci D, Langosch D, et al. Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u. EMBO J. 2014;33:2492–506.

    Article  CAS  Google Scholar 

  16. Avci D, Fuchs S, Schrul B, Fukumori A, Breker M, Frumkin I, et al. The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating transporter abundance. Mol Cell. 2014;56:630–40.

    Article  CAS  Google Scholar 

  17. Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science. 2007;318:977–80.

    Article  CAS  Google Scholar 

  18. Chen X, Wei S, Ji Y, Guo X, Yang F. Quantitative proteomics using SILAC: principles, applications, and developments. Proteomics. 2015;15:3175–92.

    Article  CAS  Google Scholar 

  19. Lam E, Martin M, Wiederrecht G. Isolation of a cDNA encoding a novel human FK506-binding protein homolog containing leucine zipper and tetratricopeptide repeat motifs. Gene. 1995;160:297–302.

    Article  CAS  Google Scholar 

  20. Shirane M, Nakayama KI. Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nat Cell Biol. 2003;5:28–37.

    Article  CAS  Google Scholar 

  21. Edlich F, Weiwad M, Erdmann F, Fanghanel J, Jarczowski F, Rahfeld JU, et al. Bcl-2 regulator FKBP38 is activated by Ca2+/calmodulin. EMBO J. 2005;24:2688–99.

    Article  CAS  Google Scholar 

  22. Das I, Craig C, Funahashi Y, Jung KM, Kim TW, Byers R, et al. Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function. J Biol Chem. 2004;279:30771–80.

    Article  CAS  Google Scholar 

  23. Murakami D, Okamoto I, Nagano O, Kawano Y, Tomita T, Iwatsubo T, et al. Presenilin-dependent gamma-secretase activity mediates the intramembranous cleavage of CD44. Oncogene. 2003;22:1511–6.

    Article  CAS  Google Scholar 

  24. Cespedes MV, Larriba MJ, Pavon MA, Alamo P, Casanova I, Parreno M, et al. Site-dependent E-cadherin cleavage and nuclear translocation in a metastatic colorectal cancer model. Am J Pathol. 2010;177:2067–79.

    Article  CAS  Google Scholar 

  25. Guan M, Su L, Yuan YC, Li H, Chow WA. Nelfinavir and nelfinavir analogs block site-2 protease cleavage to inhibit castration-resistant prostate cancer. Sci Rep. 2015;5:9698.

    Article  CAS  Google Scholar 

  26. Song W, Liu W, Zhao H, Li S, Guan X, Ying J, et al. Rhomboid domain containing 1 promotes colorectal cancer growth through activation of the EGFR signalling pathway. Nat Commun. 2015;6:8022.

    Article  CAS  Google Scholar 

  27. Wahlstrom AM, Cutts BA, Karlsson C, Andersson KM, Liu M, Sjogren AK, et al. Rce1 deficiency accelerates the development of K-RAS-induced myeloproliferative disease. Blood. 2007;109:763–8.

    Article  CAS  Google Scholar 

  28. Fong S, Mounkes L, Liu Y, Maibaum M, Alonzo E, Desprez PY, et al. Functional identification of distinct sets of antitumor activities mediated by the FKBP gene family. Proc Natl Acad Sci USA. 2003;100:14253–8.

    Article  CAS  Google Scholar 

  29. Choi MS, Min SH, Jung H, Lee JD, Lee TH, Lee HK, et al. The essential role of FKBP38 in regulating phosphatase of regenerating liver 3 (PRL-3) protein stability. Biochem Biophys Res Commun. 2011;406:305–9.

    Article  CAS  Google Scholar 

  30. Barth S, Edlich F, Berchner-Pfannschmidt U, Gneuss S, Jahreis G, Hasgall PA, et al. Hypoxia-inducible factor prolyl-4-hydroxylase PHD2 protein abundance depends on integral membrane anchoring of FKBP38. J Biol Chem. 2009;284:23046–58.

    Article  CAS  Google Scholar 

  31. Wei JW, Cai JQ, Fang C, Tan YL, Huang K, Yang C, et al. Signal peptide peptidase, encoded by HM13, contributes to tumor progression by affecting EGFRvIII secretion profiles in glioblastoma. CNS Neurosci Ther. 2017;23:257–65.

    Article  CAS  Google Scholar 

  32. Hwang HW, Lee JR, Chou KY, Suen CS, Hwang MJ, Chen C, et al. Oligomerization is crucial for the stability and function of heme oxygenase-1 in the endoplasmic reticulum. J Biol Chem. 2009;284:22672–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ministry of Science and Technology Taiwan (MOST 103-2320-B-001-013-MY3) and Institute of Biomedical Sciences, Academia Sinica.

Author information

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Fu-Fei Hsu, Yi-Tai Chou, Ming-Tsai Chiang, Fu-An Li & Lee-Young Chau

  2. Cancer Center, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

    Chi-Tai Yeh & Wei-Hwa Lee

Authors
  1. Fu-Fei Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-Tai Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming-Tsai Chiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fu-An Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chi-Tai Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Hwa Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lee-Young Chau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lee-Young Chau.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hsu, FF., Chou, YT., Chiang, MT. et al. Signal peptide peptidase promotes tumor progression via facilitating FKBP8 degradation. Oncogene 38, 1688–1701 (2019). https://doi.org/10.1038/s41388-018-0539-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0539-y

This article is cited by

Search

Advanced search

Quick links