Prohibitin regulates mTOR pathway via interaction with FKBP8


The ability of tumor cells to sustain continuous proliferation is one of the major characteristics of cancer. The activation of oncogenes and the mutation or inactivation of tumor suppressor genes ensure the rapid proliferation of tumor cells. The PI3K-Akt-mTOR axis is one of the most frequently modified signaling pathways whose activation sustains cancer growth. Unsurprisingly, it is also one of the most commonly attempted targets for cancer therapy. FK506 binding protein 8 (FKBP8) is an intrinsic inhibitor of mTOR kinase that also exerts an anti-apoptotic function. We aimed to explain these contradictory aspects of FKBP8 in cancer by identifying a “switch” type regulator. We identified through immunoprecipitation-mass spectrometry-based proteomic analysis that the mitochondrial protein prohibitin 1 (PHB1) specifically interacts with FKBP8. Furthermore, the downregulation of PHB1 inhibited the proliferation of ovarian cancer cells and the mTOR signaling pathway, whereas the FKBP8 level in the mitochondria was substantially reduced. Moreover, concomitant with these changes, the interaction between FKBP8 and mTOR substantially increased in the absence of PHB1. Collectively, our finding highlights PHB1 as a potential regulator of FKBP8 because of its subcellular localization and mTOR regulating role.

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


  1. 1.

    Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S, Yonezawa K. Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 2006; 25(48): 6361–6372

    CAS  Article  Google Scholar 

  2. 2.

    Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12(1): 9–22

    CAS  Article  Google Scholar 

  3. 3.

    Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, Jiang Y. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 2007; 318(5852): 977–980

    CAS  Article  Google Scholar 

  4. 4.

    Barik S. Immunophilins: for the love of proteins. Cell Mol Life Sci 2006; 63(24): 2889–2900

    CAS  Article  Google Scholar 

  5. 5.

    Edlich F, Lücke C. From cell death to viral replication: the diverse functions of the membrane-associated FKBP38. Curr Opin Pharmacol 2011; 11(4): 348–353

    CAS  Article  Google Scholar 

  6. 6.

    Shirane-Kitsuji M, Nakayama KI. Mitochondria: FKBP38 and mitochondrial degradation. Int J Biochem Cell Biol 2014; 51: 19–22

    CAS  Article  Google Scholar 

  7. 7.

    Choi BH, Feng L, Yoon HS. FKBP38 protects Bcl-2 from caspase-dependent degradation. J Biol Chem 2010; 285(13): 9770–9779

    CAS  Article  Google Scholar 

  8. 8.

    Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 1995; 17(6): 584–591

    CAS  Article  Google Scholar 

  9. 9.

    Proud CG. Cell signaling. imTOR, unleashed. Science 2007; 318 (5852): 926–927

    CAS  Article  Google Scholar 

  10. 10.

    Shirane M, Nakayama KI. Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nat Cell Biol 2003; 5(1): 28–37

    CAS  Article  Google Scholar 

  11. 11.

    Haupt K, Jahreis G, Linnert M, Maestre-Martínez M, Malesevic M, Pechstein A, Edlich F, Lücke C. The FKBP38 catalytic domain binds to Bcl-2 via a charge-sensitive loop. J Biol Chem 2012; 287 (23): 19665–19673

    CAS  Article  Google Scholar 

  12. 12.

    Tavernarakis N, Driscoll M, Kyrpides NC. The SPFH domain: implicated in regulating targeted protein turnover in stomatins and other membrane-associated proteins. Trends Biochem Sci 1999; 24 (11): 425–427

    CAS  Article  Google Scholar 

  13. 13.

    Artal-Sanz M, Tavernarakis N. Prohibitin and mitochondrial biology. Trends Endocrinol Metab 2009; 20(8): 394–401

    CAS  Article  Google Scholar 

  14. 14.

    McClung JK, Danner DB, Stewart DA, Smith JR, Schneider EL, Lumpkin CK, Dell’Orco RT, Nuell MJ. Isolation of a cDNA that hybrid selects antiproliferative mRNA from rat liver. Biochem Biophys Res Commun 1989; 164(3): 1316–1322

    CAS  Article  Google Scholar 

  15. 15.

    Liu P, Xu Y, Zhang W, Li Y, Tang L, Chen W, Xu J, Sun Q, Guan X. Prohibitin promotes androgen receptor activation in ER-positive breast cancer. Cell Cycle 2017; 16(8): 776–784

    CAS  Article  Google Scholar 

  16. 16.

    Du MD, He KY, Qin G, Chen J, Li JY. Adriamycin resistance-associated prohibitin gene inhibits proliferation of human osteosarcoma MG63 cells by interacting with oncogenes and tumor suppressor genes. Oncol Lett 2016; 12(3):1994–2000

    CAS  Article  Google Scholar 

  17. 17.

    Liao Q, Guo X, Li X, Xiong W, Li X, Yang J, Chen P, Zhang W, Yu H, Tang H, Deng M, Liang F, Wu M, Luo Z, Wang R, Zeng X, Zeng Z, Li G. Prohibitin is an important biomarker for nasopharyngeal carcinoma progression and prognosis. Eur J Cancer Prev 2013; 22 (1): 68–76

    CAS  Article  Google Scholar 

  18. 18.

    Lu JJ, Lu DZ, Chen YF, Dong YT, Zhang JR, Li T, Tang ZH, Yang Z. Proteomic analysis of hepatocellular carcinoma HepG2 cells treated with platycodin D. Chin J Nat Med 2015; 13(9): 673–679

    CAS  PubMed  Google Scholar 

  19. 19.

    Cao Y, Liang H, Zhang F, Luan Z, Zhao S, Wang XA, Liu S, Bao R, Shu Y, Ma Q, Zhu J, Liu Y. Prohibitin overexpression predicts poor prognosis and promotes cell proliferation and invasion through ERK pathway activation in gallbladder cancer. J Exp Clin Cancer Res 2016; 35: 68

    Article  Google Scholar 

  20. 20.

    Jiang L, Dong P, Zhang Z, Li C, Li Y, Liao Y, Li X, Wu Z, Guo S, Mai S, Xie D, Liu Z, Zhou F. Akt phosphorylates prohibitin 1 to mediate its mitochondrial localization and promote proliferation of bladder cancer cells. Cell Death Dis 2015; 6(2): e1660

    CAS  Article  Google Scholar 

  21. 21.

    Dai Z, Yin J, He H, Li W, Hou C, Qian X, Mao N, Pan L. Mitochondrial comparative proteomics of human ovarian cancer cells and their platinum-resistant sublines. Proteomics 2010; 10(21): 3789–3799

    CAS  Article  Google Scholar 

  22. 22.

    Wu TF, Wu H, Wang YW, Chang TY, Chan SH, Lin YP, Liu HS, Chow NH. Prohibitin in the pathogenesis of transitional cell bladder cancer. Anticancer Res 2007; 27(2): 895–900

    CAS  PubMed  Google Scholar 

  23. 23.

    El-Etreby NM, Ghazy AA, Rashad R. Prohibitin: targeting peptide coupled to ovarian cancer, luteinization and TGF-β pathways. J Ovarian Res 2017; 10(1): 28

    Article  Google Scholar 

  24. 24.

    Rajalingam K, Wunder C, Brinkmann V, Churin Y, Hekman M, Sievers C, Rapp UR, Rudel T. Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration. Nat Cell Biol 2005; 7(8): 837–843

    CAS  Article  Google Scholar 

  25. 25.

    Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell 2009; 138(2): 389–403

    CAS  Article  Google Scholar 

  26. 26.

    Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature 2010; 466(7302): 68–76

    CAS  Article  Google Scholar 

  27. 27.

    Saita S, Shirane M, Nakayama KI. Selective escape of proteins from the mitochondria during mitophagy. Nat Commun 2013; 4(1): 1410

    Article  Google Scholar 

  28. 28.

    Uhlenbrock K, Weiwad M, Wetzker R, Fischer G, Wittinghofer A, Rubio I. Reassessment of the role of FKBP38 in the Rheb/mTORC1 pathway. FEBS Lett 2009; 583(6): 965–970

    CAS  Article  Google Scholar 

  29. 29.

    Wang X, Fonseca BD, Tang H, Liu R, Elia A, Clemens MJ, Bommer UA, Proud CG. Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling. J Biol Chem 2008; 283(45): 30482–3092

    CAS  Article  Google Scholar 

  30. 30.

    Hsu FF, Chou YT, Chiang MT, Li FA, Yeh CT, Lee WH, Chau LY. Signal peptide peptidase promotes tumor progression via facilitating FKBP8 degradation. Oncogene 2019; 38(10): 1688–1701

    CAS  Article  Google Scholar 

  31. 31.

    Fong S, Mounkes L, Liu Y, Maibaum M, Alonzo E, Desprez PY, Thor AD, Kashani-Sabet M, Debs RJ. Functional identification of distinct sets of antitumor activities mediated by the FKBP gene family. Proc Natl Acad Sci U S A 2003; 100(24): 14253–14258

    CAS  Article  Google Scholar 

  32. 32.

    Barth S, Nesper J, Hasgall PA, Wirthner R, Nytko KJ, Edlich F, Katschinski DM, Stiehl DP, Wenger RH, Camenisch G. The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability. Mol Cell Biol 2007; 27(10): 3758–3768

    CAS  Article  Google Scholar 

  33. 33.

    Patel N, Chatterjee SK, Vrbanac V, Chung I, Mu CJ, Olsen RR, Waghorne C, Zetter BR. Rescue of paclitaxel sensitivity by repression of prohibitin 1 in drug-resistant cancer cells. Proc Natl Acad Sci U S A 2010; 107(6):2503–2508

    CAS  Article  Google Scholar 

  34. 34.

    Bhujabal Z, Birgisdottir ÅB, Sjøttem E, Brenne HB, Øvervatn A, Habisov S, Kirkin V, Lamark T, Johansen T. FKBP8 recruits LC3A to mediate Parkin-independent mitophagy. EMBO Rep 2017; 18(6): 947–961 PubMed

    CAS  Article  Google Scholar 

  35. 35.

    Wei Y, Chiang WC, Sumpter R, Jr, Mishra P, Levine B. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 2017; 168(1–2): 224–238.e10

    CAS  Article  Google Scholar 

Download references


This work was funded by Shanghai Pujiang Program (No.18PJ140-6700).

Author information



Corresponding authors

Correspondence to Bruce Zetter or Yingjie Xu.

Additional information

Compliance with ethics guidelines

Jiahui Zhang, Yanan Yin, Jiahui Wang, Jingjing Zhang, Hua Liu, Weiwei Feng, Wen Yang, Bruce Zetter, and Yingjie Xu declare no conflict of interest. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 as revised in 2000. Additional informed consent was obtained from all patients, whose identifying information is included in this article.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Yin, Y., Wang, J. et al. Prohibitin regulates mTOR pathway via interaction with FKBP8. Front. Med. (2020).

Download citation


  • prohibitin 1
  • FKBP8
  • mTOR
  • cell proliferation
  • cancer