{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DEPTOR is a naturally occurring inhibitor of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) that plays a multifaceted role in controlling cell growth, survival, metabolism, and autophagy. At basal levels, DEPTOR binds to mTOR complexes and suppresses their kinase activity. Its expression is tightly regulated, as mTOR-mediated feedback loops and growth‐factor signals trigger phosphorylation events that promote DEPTOR recognition by SCF (βTrCP) E3 ubiquitin ligases, resulting in its ubiquitination and proteasomal degradation (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n This regulated turnover of DEPTOR is crucial for proper mTOR activation: loss of DEPTOR relieves its inhibitory constraint, thereby promoting mTORC1 and mTORC2 signaling. In many cancers, low DEPTOR levels are associated with hyperactive mTOR signaling and enhanced cell growth and survival; however, paradoxically, in a subset of multiple myeloma characterized by specific genetic translocations, high DEPTOR levels are maintained to sustain PI3K/Akt activity and support tumor cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, somatic mutations in mTOR can reduce its affinity for DEPTOR, contributing to pathway hyperactivation in various tumor types."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, in the context of autophagy regulation, stabilization of DEPTOR contributes to mTOR inactivation and autophagy induction, a process that is tightly timed by Cullin ligase–mediated degradation of key autophagy regulators."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n DEPTOR also functions as a mediator of cross‐talk between the mTOR and Akt pathways. For instance, under certain metabolic conditions, DEPTOR is upregulated and facilitates Akt activation via a feedback mechanism that modulates the insulin signaling cascade and glycolytic metabolism in skeletal muscle."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Conversely, acute mitogenic stimulation leads to rapid dissociation of DEPTOR from mTORC1—mediated by phosphatidic acid species with unsaturated fatty acyl chains—thus permitting full activation of the mTOR pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, in the setting of oncogenic processes beyond multiple myeloma, such as in certain lung cancers, modulation of DEPTOR levels is critical. For example, interference with DEPTOR degradation can dampen mTOR signaling and contribute to growth suppression, underscoring its potential as a therapeutic target when combined with other interventions that manipulate the ubiquitin–proteasome system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In adipogenesis, DEPTOR induction by glucocorticoids promotes adipose tissue expansion by enhancing the Akt/PPAR-γ proadipogenic axis, thereby linking DEPTOR to metabolic regulation and obesity-related phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yongchao Zhao, Xiufang Xiong, Yi Sun "}, {"type": "b", "children": [{"type": "t", "text": "DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2011.08.029"}], "href": "https://doi.org/10.1016/j.molcel.2011.08.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22017876"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22017876"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Daming Gao, Hiroyuki Inuzuka, Meng-Kwang Marcus Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2011.08.030"}], "href": "https://doi.org/10.1016/j.molcel.2011.08.030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22017875"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22017875"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Shanshan Duan, Jeffrey R Skaar, Shafi Kuchay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2011.09.005"}], "href": "https://doi.org/10.1016/j.molcel.2011.09.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22017877"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22017877"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Timothy R Peterson, Mathieu Laplante, Carson C Thoreen, et al. 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