DEPTOR, an MTOR Inhibitor, is a Physiological Substrate of SCF(βTrCP) E3 Ubiquitin Ligase and Regulates Survival and Autophagy

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Oct 25

PMID 22017876

Citations 162

Authors

Yongchao Zhao

Xiufang Xiong

Yi Sun

Affiliations

Soon will be listed here.

Abstract

DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCF(βTrCP) E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F box protein, βTrCP, via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by βTrCP. DEPTOR half-life is shortened by βTrCP but extended by a dominant-negative mutant of βTrCP, by RSK1/S6K1 inhibition, and by βTrCP degron site mutations. Biologically, DEPTOR accumulation upon βTrCP knockdown inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR accumulates upon glucose deprivation and mTOR inhibition to induce autophagy. Thus, βTrCP-DEPTOR-mTOR intertwine to regulate cell survival and autophagy.

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References

Gu Q, Bowden G, Normolle D, Sun Y . SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IkappaB-alpha/NF-kappaB. J Cell Biol. 2007; 178(6):1009-23. PMC: 2064624. DOI: 10.1083/jcb.200612067. View

Levine B, Klionsky D . Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004; 6(4):463-77. DOI: 10.1016/s1534-5807(04)00099-1. View

Sarbassov D, Ali S, Sabatini D . Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005; 17(6):596-603. DOI: 10.1016/j.ceb.2005.09.009. View

Deshaies R, Joazeiro C . RING domain E3 ubiquitin ligases. Annu Rev Biochem. 2009; 78:399-434. DOI: 10.1146/annurev.biochem.78.101807.093809. View

Vucicevic L, Misirkic M, Janjetovic K, Vilimanovich U, Sudar E, Isenovic E . Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. Autophagy. 2010; 7(1):40-50. DOI: 10.4161/auto.7.1.13883. View

Jung C, Ro S, Cao J, Otto N, Kim D . mTOR regulation of autophagy. FEBS Lett. 2010; 584(7):1287-95. PMC: 2846630. DOI: 10.1016/j.febslet.2010.01.017. View

Frescas D, Pagano M . Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer. 2008; 8(6):438-49. PMC: 2711846. DOI: 10.1038/nrc2396. View

Jin J, Cardozo T, Lovering R, Elledge S, Pagano M, Harper J . Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 2004; 18(21):2573-80. PMC: 525538. DOI: 10.1101/gad.1255304. View

Thoreen C, Kang S, Chang J, Liu Q, Zhang J, Gao Y . An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009; 284(12):8023-32. PMC: 2658096. DOI: 10.1074/jbc.M900301200. View

10.

Swaroop M, Wang Y, Miller P, Duan H, Jatkoe T, Madore S . Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: chip profiling implicates its role in cell cycle regulation. Oncogene. 2000; 19(24):2855-66. DOI: 10.1038/sj.onc.1203635. View

11.

Willems A, Schwab M, Tyers M . A hitchhiker's guide to the cullin ubiquitin ligases: SCF and its kin. Biochim Biophys Acta. 2004; 1695(1-3):133-70. DOI: 10.1016/j.bbamcr.2004.09.027. View

12.

Dehan E, Bassermann F, Guardavaccaro D, Vasiliver-Shamis G, Cohen M, Lowes K . betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis. Mol Cell. 2009; 33(1):109-16. PMC: 2655121. DOI: 10.1016/j.molcel.2008.12.020. View

13.

Winston J, Strack P, Chu C, Elledge S, Harper J . The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev. 1999; 13(3):270-83. PMC: 316433. DOI: 10.1101/gad.13.3.270. View

14.

Kondo Y, Kanzawa T, Sawaya R, Kondo S . The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005; 5(9):726-34. DOI: 10.1038/nrc1692. View

15.

Tan M, Gallegos J, Gu Q, Huang Y, Li J, Jin Y . SAG/ROC-SCF beta-TrCP E3 ubiquitin ligase promotes pro-caspase-3 degradation as a mechanism of apoptosis protection. Neoplasia. 2007; 8(12):1042-54. PMC: 1783718. DOI: 10.1593/neo.06568. View

16.

Gu Q, Tan M, Sun Y . SAG/ROC2/Rbx2 is a novel activator protein-1 target that promotes c-Jun degradation and inhibits 12-O-tetradecanoylphorbol-13-acetate-induced neoplastic transformation. Cancer Res. 2007; 67(8):3616-25. DOI: 10.1158/0008-5472.CAN-06-4020. View

17.

Dorrello N, Peschiaroli A, Guardavaccaro D, Colburn N, Sherman N, Pagano M . S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006; 314(5798):467-71. DOI: 10.1126/science.1130276. View

18.

Jia L, Yang J, Hao X, Zheng M, He H, Xiong X . Validation of SAG/RBX2/ROC2 E3 ubiquitin ligase as an anticancer and radiosensitizing target. Clin Cancer Res. 2010; 16(3):814-24. PMC: 2819752. DOI: 10.1158/1078-0432.CCR-09-1592. View

19.

Nakayama K, Nakayama K . Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006; 6(5):369-81. DOI: 10.1038/nrc1881. View

20.

Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell. 2008; 132(1):27-42. PMC: 2696814. DOI: 10.1016/j.cell.2007.12.018. View