ArticleProceedings of the National Academy of Sciences of the United States of America2019
Phosphorylation of DEPDC5, a component of the GATOR1 complex, releases inhibition of mTORC1 and promotes tumor growth.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- A systematic review on active sites and functions of PIM-1 protein.Human cell · 2022Pooled it
- Structure and function of the yeast amino acid-sensing SEAC-EGOC supercomplex.Nature structural & molecular biology · 2026Article
- α-hederin decreases the glycolysis level in intestinal epithelial cells via SNX10-mediated DEPDC5 degradation.Journal of pharmaceutical analysis · 2025Article
- AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.Developmental cell · 2025Article
- Article
- RAGA prevents tumor immune evasion of LUAD by promoting CD47 lysosome degradation.Communications biology · 2023Article
- Specific genetic aberrations of parathyroid in Chinese patients with tertiary hyperparathyroidism using whole-exome sequencing.Frontiers in endocrinology · 2023Article
- Correlation of DEPDC5 rs1012068 and rs5998152 Polymorphisms with Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.Journal of oncology · 2023Review
- Synthesis of 2-Oxoquinoline Derivatives as Dual Pim and mTORC Protein Kinase Inhibitors.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2022Article
- SEA and GATOR 10 Years Later.Cells · 2021Review
- EDC3 phosphorylation regulates growth and invasion through controlling P-body formation and dynamics.EMBO reports · 2021Article
- The Roles of Post-Translational Modifications on mTOR Signaling.International journal of molecular sciences · 2021Review
- Regulation of Body Size and Growth Control.Genetics · 2020Review
- Structural Insights into TOR Signaling.Genes · 2020Review
- PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth.Molecular oncology · 2020Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The Pim and AKT serine/threonine protein kinases are implicated as drivers of cancer. Their regulation of tumor growth is closely tied to the ability of these enzymes to mainly stimulate protein synthesis by activating mTORC1 (mammalian target of rapamycin complex 1) signaling, although the exact mechanism is not completely understood. mTORC1 activity is normally suppressed by amino acid starvation through a cascade of multiple regulatory protein complexes, e.g., GATOR1, GATOR2, and KICSTOR, that reduce the activity of Rag GTPases. Bioinformatic analysis revealed that DEPDC5 (DEP domain containing protein 5), a component of GATOR1 complex, contains Pim and AKT protein kinase phosphorylation consensus sequences. DEPDC5 phosphorylation by Pim and AKT kinases was confirmed in cancer cells through the use of phospho-specific antibodies and transfection of phospho-inactive DEPDC5 mutants. Consistent with these findings, during amino acid starvation the elevated expression of Pim1 overcame the amino acid inhibitory protein cascade and activated mTORC1. In contrast, the knockout of DEPDC5 partially blocked the ability of small molecule inhibitors against Pim and AKT kinases both singly and in combination to suppress tumor growth and mTORC1 activity in vitro and in vivo. In animal experiments knocking in a glutamic acid (S1530E) in DEPDC5, a phospho mimic, in tumor cells induced a significant level of resistance to Pim and the combination of Pim and AKT inhibitors. Our results indicate a phosphorylation-dependent regulatory mechanism targeting DEPDC5 through which Pim1 and AKT act as upstream effectors of mTORC1 to facilitate proliferation and survival of cancer cells.
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