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

Sato, Tatsuhiro; Akasu, Hitomi; Shimono, Wataru; Matsu, Chisa; Fujiwara, Yuki; Shibagaki, Yoshio; Heard, Jeffrey J.; Tamanoi, Fuyuhiko; Hattori, Satoshi

doi:10.1074/jbc.m114.592402

Cited by 33 publications

(31 citation statements)

References 33 publications

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“…Thus, hyper‐activation of mTORC1 induces pyrimidine synthesis to promote cell growth and cell cycle progression. The mTORC1‐independent binding of CAD to GTP‐bound Rheb was also reported, suggesting that CAD is regulated at multiple levels in TSC gene‐deficient tumors …”

Section: Tsc: a Multi‐organ Disorder With A Defect In The Tumor Supprmentioning

confidence: 84%

Mourning Dr. Alfred G. Knudson: the two‐hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

Hino

Kobayashi

2017

Cancer Science

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On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two‐hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor‐predisposing syndromes. To understand the molecular mechanism of two‐hit‐initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor‐predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1/Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1‐independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research.

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Section: Tsc: a Multi‐organ Disorder With A Defect In The Tumor Supprmentioning

confidence: 84%

Mourning Dr. Alfred G. Knudson: the two‐hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

Hino

Kobayashi

2017

Cancer Science

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“…Similarly, RAD9 homolog A (RAD9A), Ras-homolog are represented in the figure and inhibition and activation of these reactions by regulators is represented by (−) and (+) signs, respectively. Subunit information is indicated as subscript for the enzymes enriched in brain pseudogene 1 (RHEBP1), Ras homolog enriched in brain like 1 (RHEBL1) interaction with CAD, increases the catalytic activity of CAD (Lindsey-Boltz et al 2004;Sato et al 2015) and sirtuin 4 (SIRT4) interaction inhibits GLUD1 and GLUD2 (Haigis et al 2006). …”

Section: Regulation Of Glutamate Metabolic Pathwaymentioning

confidence: 99%

A pathway map of glutamate metabolism

Yelamanchi

Jayaram

Thomas

et al. 2015

J. Cell Commun. Signal.

124

100

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Glutamate metabolism plays a vital role in biosynthesis of nucleic acids and proteins. It is also associated with a number of different stress responses. Deficiency of enzymes involved in glutamate metabolism is associated with various disorders including gyrate atrophy, hyperammonemia, hemolytic anemia, γ-hydoxybutyric aciduria and 5-oxoprolinuria. Here, we present a pathway map of glutamate metabolism representing metabolic intermediates in the pathway, 107 regulator molecules, 9 interactors and 3 types of post-translational modifications. This pathway map provides detailed information about enzyme regulation, protein-enzyme interactions, post-translational modifications of enzymes and disorders due to enzyme deficiency. The information included in the map was based on published experimental evidence reported from mammalian systems.

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“…As expected for effectors of small GTPases, CAD specifically interacts with the GTP‐bound active form of Rheb, and this interaction is affected by mutations in the effector domain of Rheb. Although mTORC1 activation of S6K induces phosphorylation and activation of CAD, the study suggests that Rheb can also regulate pyrimidine nucleotide biosynthesis through an mTORC1‐independent mechanism . Relevance of Rheb on pyrimidine nucleotide biosynthesis is only supported by studies in Tsc2 ‐null cells .…”

Section: Mtorc1‐independent Rheb Functions Role In Cancer?mentioning

confidence: 97%

“…Other mTORC1‐independent Rheb functions include activation of Notch signaling and activation of CAD (carbamoyl‐phosphate synthetase 2, aspartate transcarbamoylase and dihydroorotase) . Rheb was found to activate Notch in Drosophila and TSC cells.…”

Section: Mtorc1‐independent Rheb Functions Role In Cancer?mentioning

confidence: 99%

Rheb signaling and tumorigenesis: mTORC1 and new horizons

Armijo

Campos

Fuentes-Villalobos

et al. 2015

Intl Journal of Cancer

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Rheb is a conserved small GTPase that belongs to the Ras superfamily, and is mainly involved in activation of cell growth through stimulation of mTORC1 activity. Because deregulation of the Rheb/mTORC1 signaling is associated with proliferative disorders and cancer, inhibition of mTORC1 has been therapeutically approached. Although this therapy has proven antitumor activity, its efficacy is not as expected. Here, we will review the main work on the identification of the role of Rheb in cell growth, and on the relevance of Rheb in proliferative disorders, including cancer. We will also review the Rheb functions that could explain tumor resistance to therapies with mTORC1 inhibitors, and will mainly focus our discussion on mTORC1‐independent Rheb functions that could also be implicated in cancer cell survival and tumorigenesis. The current progress on the understanding of the noncanonical Rheb functions prompts future studies to establish their relevance in cancer and in the context of current cancer therapies.

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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

Abstract: Background: Rheb activates mTORC1 to stimulate mRNA translation. Results: Rheb binds to CAD and activates CPSase activity. Conclusion: Rheb affects intracellular pyrimidine nucleotide pools. Significance: Our results provide a new mechanism that TSC/Rheb signaling regulates cell growth.

Cited by 33 publications

References 33 publications

Mourning Dr. Alfred G. Knudson: the two‐hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

Mourning Dr. Alfred G. Knudson: the two‐hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

A pathway map of glutamate metabolism

Rheb signaling and tumorigenesis: mTORC1 and new horizons

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