MTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR

Department of Pathology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
Molecular cell (Impact Factor: 14.02). 10/2011; 44(2):317-24. DOI: 10.1016/j.molcel.2011.09.005
Source: PubMed


DEPTOR is a recently identified inhibitor of the mTOR kinase that is highly regulated at the posttranslational level. In response to mitogens, we found that DEPTOR was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the F box protein βTrCP, with consequent proteasomal degradation of DEPTOR. Phosphorylation of the βTrCP degron in DEPTOR is executed by CK1α after a priming phosphorylation event mediated by either the mTORC1 or mTORC2 complexes. Blocking the βTrCP-dependent degradation of DEPTOR via βTrCP knockdown or expression of a stable DEPTOR mutant that is unable to bind βTrCP results in mTOR inhibition. Our findings reveal that mTOR cooperates with CK1α and βTrCP to generate an auto-amplification loop to promote its own full activation. Moreover, our results suggest that pharmacologic inhibition of CK1 may be a viable therapeutic option for the treatment of cancers characterized by activation of mTOR-signaling pathways.

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    • "). DEPTOR was phosphorylated by casein kinase 1 alpha, facilitating ubiquitylation by the F box protein SCF (βTrCP) (Duan et al., 2011). Although post-translational regulation of DEPTOR expression has been investigated, transcriptional regulation of DEPTOR remains unclear. "
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    ABSTRACT: It has been noticed that crosstalk between androgen receptor (AR) and mammalian target of rapamycin (mTOR) signaling pathways plays a crucial role in the proliferation of prostate cancer cells. To clarify this mechanism, we focused on DEPTOR, a naturally occurring inhibitor of mTOR. The treatment of a human AR-positive prostate cancer cell line, LNCaP, with the AR-agonist dihydrotestosterone (DHT) repressed DEPTOR mRNA expression in a time-dependent manner. This repression was abrogated by treatment with the AR-antagonist bicalutamide. Knockdown of DEPTOR mRNA by siRNA resulted in the increased phosphorylation of 70 kDa ribosomal protein S6 kinase 1 (S6K), a substrate of mTORC1, accompanied by the elevated expression of cyclin D1, a positive regulator of cell proliferation. Furthermore, the ChIP assay demonstrated that AR could bind to AR-responsible element-like region within the 4th intron of the DEPTOR gene. The amount of acetylated histone H3 (Lys9, Lys14) was reduced by the DHT treatment in this region. Taken together, these results propose that AR-dependent prostate cancer cell proliferation requires decreased DEPTOR transcription directly controlled by AR.
    Preview · Article · Nov 2015 · The Journal of Toxicological Sciences
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    • "Finally, in 2009, mTOR was found to associate with a 48 kDa protein, named DEPTOR (Dishevelled, Egl-10, Pleckstrin domain protein interacting with mTOR), which inhibited both mTORC1 and mTORC2 signaling (Peterson et al. 2009). Later, it was shown that activated mTORC1 and mTORC2 could phosphorylate DEPTOR, leading to its ubiquitination by the E3 ligase complex, SCF TrCP, and subsequent degradation by the ubiquitin proteasome system (Duan et al. 2011; Gao et al. 2011; Zhao et al. 2011). Thus, activated mTORC1 and mTORC2 could mediate the degradation of DEPTOR and, in effect, create a positive feedback loop that further enhanced mTORC1 and mTORC2 signaling. "
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    • "On phosphorylation on β-TrCP binding motif, DEPTOR is bound to β-TrCP, which recruits E2-loaded RBX1-Cullin 1 complex, catalyzing ubiquitin transfer from E2 to DEPTOR. Multiple runs of this E1/E2/ E3–mediated chain reaction cause DEPTOR polyubiquitination, which is then recognized by the 26S proteasome for subsequent degradation (Figure 3B) [22] [33] [37]. "
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