Article

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: 14.46). 10/2011; 44(2):317-24. DOI: 10.1016/j.molcel.2011.09.005
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ABSTRACT 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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Available from: Naama Kanarek, Jan 29, 2014
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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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    ABSTRACT: The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation, survival, and autophagy. The mTOR pathway is frequently activated in many human cancers, mainly resulting from alterations in the upstream regulators, such as phosphoinositide 3-kinase (PI3K)/AKT activation, PTEN loss or dysregulation of mTOR-negative regulators (e.g., TSC1/2), leading to uncontrolled proliferation. Thus, inhibiting the PI3K/AKT/mTOR pathways is widely considered as an effective approach for targeted cancer therapy. Recently, we and others found that DEPTOR, a naturally occurring inhibitor of both mTORC1 and mTORC2, was degraded by SCF (Skp1-Cullin-F box proteins) E3 ubiquitin ligase, the founding member of cullin-RING-ligases (CRLs), resulting in mTOR activation and cell proliferation. In addition to DEPTOR, previous studies have demonstrated that several other negative regulators of mTOR pathway are also substrates of CRL/SCF E3s. Thus, targeting CRL/SCF E3s is expected to cause the accumulation of these mTOR signal inhibitors to effectively block the mTOR pathway. In this review, we will discuss mTOR signaling pathway, how DEPTOR regulates mTOR/AKT axis, thus acting as a tumor suppressor or oncogene in some cases, how DEPTOR is ubiquitinated and degraded by SCF(β-TrCP) E3, and how MLN4924, a small-molecule indirect inhibitor of CRL/SCF E3 ligases through blocking cullin neddylation, might be useful as a novel approach of mTOR pathway targeting for cancer therapy.
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    • "Because DEPTOR binds and inhibits mTOR, whose activity is mostly hyperactivated in many human tumors, DEPTOR is considered as a tumor suppressor protein. Indeed, down-regulation of DEPTOR has been found in many types of human cancers [17] [47]. However , DEPTOR has been found to be overexpressed in many other tumor types including breast cancer, prostate cancer, chronic myeloid leukemia, and lung cancer [17,48–51]. "
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