ArticleThe Journal of biological chemistry2015
Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.Signal transduction and targeted therapy · 2025Review
- HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.Cell reports · 2025Article
- ASS1 inhibits liver cancer by promoting CAD ubiquitination and reversing the urea cycle and pyrimidine synthesis imbalance.Hepatology communications · 2025Article
- Vaccinia growth factor-dependent modulation of the mTORC1-CAD axis upon nutrient restriction.Journal of virology · 2025Article
- Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.International journal of molecular sciences · 2024Review
- The emerging roles of glutamine amidotransferases in metabolism and immune defense.Nucleosides, nucleotides & nucleic acids · 2024Review
- Induction by rapamycin and proliferation‑promoting activity of Hspb1 in aExperimental and therapeutic medicine · 2023Article
- Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival ofFrontiers in pharmacology · 2022Article
- Deciphering CAD: Structure and function of a mega-enzymatic pyrimidine factory in health and disease.Protein science : a publication of the Protein Society · 2021Review
- Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential.International journal of molecular sciences · 2021Review
- Modulating pyrimidine ribonucleotide levels for the treatment of cancer.Cancer & metabolism · 2020Review
- Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment.Molecular biology of the cell · 2019Article
- Review
- The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases.Frontiers in molecular neuroscience · 2019Review
- NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma.International journal of molecular sciences · 2018Review
- An oncogenic mutant of RHEB, RHEB Y35N, exhibits an altered interaction with BRAF resulting in cancer transformation.BMC cancer · 2018Article
- Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex.Cancer science · 2017Review
- A pathway map of glutamate metabolism.Journal of cell communication and signaling · 2016Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Rheb small GTPases, which consist of Rheb1 and Rheb2 (also known as RhebL1) in mammalian cells, are unique members of the Ras superfamily and play central roles in regulating protein synthesis and cell growth by activating mTOR. To gain further insight into the function of Rheb, we carried out a search for Rheb-binding proteins and found that Rheb binds to CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase), a multifunctional enzyme required for the de novo synthesis of pyrimidine nucleotides. CAD binding is more pronounced with Rheb2 than with Rheb1. Rheb binds CAD in a GTP- and effector domain-dependent manner. The region of CAD where Rheb binds is located at the C-terminal region of the carbamoyl-phosphate synthetase domain and not in the dihydroorotase and aspartate transcarbamoylase domains. Rheb stimulated carbamoyl-phosphate synthetase activity of CAD in vitro. In addition, an elevated level of intracellular UTP pyrimidine nucleotide was observed in Tsc2-deficient cells, which was attenuated by knocking down of Rheb. Immunostaining analysis showed that expression of Rheb leads to increased accumulation of CAD on lysosomes. Both a farnesyltransferase inhibitor that blocks membrane association of Rheb and knockdown of Rheb mislocalized CAD. These results establish CAD as a downstream effector of Rheb and suggest a possible role of Rheb in regulating de novo pyrimidine nucleotide synthesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.