Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

RHEB

  • Tadayuki Shimada
  • Hiroko Sugiura
  • Kanato Yamagata
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101555

Synonyms

Historical Background

Rheb (Ras homologue enriched in brain) was originally identified as a small guanosine triphosphate (GTP)-binding protein upregulated in the brain in response to electroconvulsive shock (Yamagata et al. 1994). Despite its name, Rheb protein is ubiquitously expressed in a variety of tissues. Rheb is evolutionarily conserved between yeast and humans, and it belongs to the Ras subfamily. In mammals, two different Rheb genes have been identified: Rheb and RhebL (also called Rheb1 and Rheb2, respectively). Since the Rheb GTPase was found to be regulated by the Tsc1 and Tsc2 proteins, which are responsible for the tuberous sclerosis complex (TSC) (Pan et al. 2004), Rheb functions have been extensively investigated. Moreover, Rheb has been demonstrated to activate the mammalian target of rapamycin (mTOR) signaling pathway and to regulate protein translation, cell proliferation, cell size, and metabolism.

Protein and Gene Structure

The mammalian Rheb protein consists of 184 amino acids. The mRNA coding sequence of Rheb comprises eight exons and covers approximately 40–50 kb of genome DNA. The crystal structures of Rheb bound with GTP, guanosine 5′-[beta, gamma-imido] triphosphate, or guanosine diphosphate (GDP) have been determined (Yu et al. 2005). The structure of Rheb is highly similar to those of other small GTPases, and it contains six beta strands, three alpha helices, and two short helices. Rheb consists of two domains: a GTPase domain comprising the N-terminal 169 amino acids, which binds a guanosine nucleotide, and a C-terminal membrane-targeting region (−CAAX), which is lipid-modified by farnesyl transferase. The functional domains of Rheb are shown in Fig. 1. Wild-type Rheb has very low intrinsic GTPase activity and a high basal GTP level (approximately 50%, which is more than ten fold higher than that of Ras).
RHEB, Fig. 1

Schematic illustration of Rheb protein. The functional domains on Rheb are depicted on the full length of the human protein. Representative point mutations are shown. Abbreviations: G box GTP-/GDP-binding domain, EB effector-binding domain, Sw1 switch 1 region, Sw2 switch 2 region, FA conserved sequence for farnesylation. Point mutations: Red, natural variants found in human cancer cells, activating mutations; Blue, dominant negative mutations; Black, loss of function mutations; Green, loss of membrane insertion mutation; Purple, higher basal GTP-bound form mutation

Like Ras proteins, Rheb proteins contain five “G box” regions that are involved in GTP binding and hydrolysis. In the Ras family, there are two conserved structures, called switch 1 and switch 2 regions. The switch regions are involved in the recognition and interaction with GTP/GDP, regulator proteins, and effector proteins. Rheb contains a conserved arginine residue (Arg15) at the equivalent position to glycine (Gly12) in Ras. Gly12 is highly conserved in other members of the Ras subfamily. It is located in the phosphate-binding loop (P loop), and its mutation to any other residue (except proline) impairs the intrinsic GTPase activity. However, Arg15 of Rheb may not be responsible for these properties. Wild-type Rheb can be inactivated by regulator proteins, and mutation of Arg15 does not affect its GTPase activation level. Thus, it might be possible that Arg15 is not directly involved in the GTPase activity of Rheb. The structure responsible for the decreased GTPase activity of Rheb may be the switch 2 region (Yu et al. 2005). The switch 1 regions of Ras and Rheb GTPases undergo conformational changes on GTP/GDP exchange. On the other hand, the switch 2 region of Ras assumes an α-helical conformation and undergoes a marked change during GTP/GDP cycling, whereas the switch 2 region of Rheb assumes a short-helical structure that shows a relatively stable conformation undergoing minor changes in response to GTP/GDP cycling (Yu et al. 2005). This unique stable structure of the Rheb switch 2 region causes Gln64 to be constitutively displaced from its counterpart position in Ras Gln61. Gln61 in Ras is directly involved in GTPase activity through polarization of a conserved water molecule that carries out nucleophilic attack on the gamma-phosphate of GTP. The displacement of Gln64 in Rheb causes its polar side chain to become buried inside a hydrophobic core, thus resulting in no interactions with the nucleotide or the functionally important residues at the catalytic active site (Yu et al. 2005). Thus, Gln64 is unlikely to participate in GTP hydrolysis, consistent with data indicating that the Q64L mutation does not impair the GTPase activity of Rheb, but does affect the high ratio of the GTP form to the GDP form. These data suggest that the unique switch 2 conformation is directly responsible for the low GTPase activity of Rheb and accounts for its high activation state.

Regulation of Rheb Activity

Like the activities of other G proteins, Rheb activity is regulated by switching between its GDP- and GTP-bound states. GTPase-activating proteins (GAPs) activate intrinsic GTPases of G proteins and change them into an inactive GDP-bound form. The GAPs for Rheb are Tsc1 and Tsc2 (tuberous sclerosis complex) proteins (Fig. 2a). Loss of function of Tsc1 or Tsc2 results in the constitutive activation of Rheb (Pan et al. 2004). Because Tsc1 or Tsc2 gene mutation causes tuberous sclerosis complex (TSC), Rheb function may be involved in the pathogenesis of TSC. In contrast, guanine nucleotide-exchanging factor (GEF) releases GDP from small G proteins and allows GTP binding, thus resulting in the activation of the target small G proteins. The GEF for Rheb has not yet been identified. As mentioned above, in contrast to other small G proteins, the majority of the Rheb protein is present in the GTP-bound form, and Rheb is more likely to be present in an active form in vivo.
RHEB, Fig. 2

Schematic signaling pathways of Rheb. (a) Canonical pathway. Tsc1/2 inactivates Rheb, which directly binds and activates the mTOR complex 1. (b) Bnip3 and α-/β-tubulin reciprocally regulate the Rheb activation state. Rheb activates mTORC1 via FKBP38 or PLD1. These protein functions were evaluated by mTORC1 activity, as indicated by the phosphorylation of S6K or 4E-BP1. (c) mTORC1-independent Rheb functions. GTP-Rheb phosphorylates PAK2, whereas GDP-Rheb increases syntenin degradation

Rheb has a consensus motif for farnesylation (−CAAX) in its carboxyl-terminal domain. Farnesylation is required for Rheb’s association with endomembranes, including lysosomes and mitochondria. A farnesylation-defective mutant of Rheb is incapable of promoting the normal cell cycle in yeast, thus indicating that recruitment to endomembranes is necessary for Rheb activation.

Several lines of evidence have indicated that mechanisms other than Tsc1/2 regulate Rheb activity (Fig. 2b). Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) directly interacts with Rheb but not with other Ras family proteins. Fluorescence resonance energy transfer (FRET) analysis has revealed that Bnip3 and Rheb co-localize in HEK cells. The overexpression of Bnip3 decreases the GTP-Rheb/GDP-Rheb ratio and the phosphorylation of ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in HEK cells, thus indicating that Bnip3 inhibits mTOR complex 1 (mTORC1) activity (see below). Bnip3 knockdown-induced tumorigenesis is impeded by rapamycin treatment. These results suggest that Bnip3 may inhibit Rheb-mediated mTORC1 activation (Heard et al. 2014). Although the activity of GEF toward Rheb has not been identified, soluble deacetylated α-/ß-tubulin dimer acts as a positive regulator of Rheb (Lee et al. 2013). The abundance of dimeric tubulin in the cells may be one reason why Rheb can maintain its GTP-bound form in vivo.

A recent study has revealed another regulatory system for Rheb activation. Syntenin, a PDZ domain-containing scaffold protein, preferentially interacts with the inactive form of Rheb rather than the active Rheb (Sugiura et al. 2015). The Rheb-syntenin complex is degraded by the proteasome. Because Rheb has a low intrinsic GTPase activity, this syntenin-mediated degradation mechanism may contribute to the downregulation of Rheb activity by decreasing the amount of Rheb protein (Fig. 2c).

Signaling Cascades Downstream of Rheb

Whereas other Ras family small G proteins have multiple effector proteins, Rheb has only one generally accepted effector protein, mTORC1 (Fig. 2a). mTORC1 consists minimally of mTOR, regulatory-associated protein of mTOR (raptor), and mammalian lethal with sec-thirteen 8 (mLST8). Rheb binds mTOR directly. Rheb and mTOR co-immunoprecipitate from lysates of cultured cells, and purified Rheb activates mTORC1 in vitro in a GTP-dependent manner. Furthermore, FRET and fluorescence lifetime imaging microscopy (FLIM) imaging studies have shown that Ds-Red-Rheb and EGFP-mTOR directly interact in living cells (Heard et al. 2014). Although active Rheb binds mTORC1 directly, the mechanism whereby Rheb activates mTORC1 has not been determined. Some mechanisms underlying the Rheb-mediated activation of mTORC1 have been demonstrated in several studies (Fig. 2b). One mechanism is the Rheb-mediated inhibition of FK506-binding protein 38 (FKBP38), an endogenous mTOR inhibitor. Rheb directly interacts with FKBP38 in a GTP-dependent manner, and this interaction prevents the association between FKBP38 and mTOR, thus resulting in mTORC1 activation (Bai et al. 2007). The other mechanism is that phospholipase D 1 (PLD1) mediates mTORC1 activation by Rheb. It interacts with PLD1 and enhances the production of phosphatidic acid (PA) by PLD1 (Heard et al. 2014). Because PA stabilizes mTOR and activates mTORC1, Rheb-mediated PLD1 activation may partially account for the mechanism of Rheb’s activation of mTORC1.

Although mTORC1 is a generally accepted effector protein for Rheb, compelling studies have indicated that Rheb has mTORC1-independent target proteins (Fig. 2c). One target other than mTOR is p21-activated kinase 2 (PAK2). PAK2 is phosphorylated in a Rheb-dependent manner, and rapamycin treatment does not affect PAK2 phosphorylation. Activated PAK2 enhances the motility of fibroblasts (Alves et al. 2015). The other target is syntenin. As described above, the Rheb-GDP/syntenin complex is degraded by the proteasome (Sugiura et al. 2015). When Rheb is in a GTP-bound form, syntenin is easily dissociated from Rheb and is not likely to be degraded by the proteasome. Accumulated syntenin binds to syndecan-2 and ephrinB3, thus resulting in a decrease and an increase in spine synapses and dendritic shaft synapses, respectively. This mechanism may explain the impaired synapse formation found in TSC neurons.

Localization

Rheb is considered to reside on the cytoplasmic surface of the lysosome but not on the plasma membrane (Sancak et al. 2007). Rheb is anchored to endomembranes, particularly to lysosomes, via its prenylated C-terminal CAAX box motif. Rheb GAP is composed of Tsc1, Tsc2, and Tre2-Bub2-Cdc16 domain family member 7 (TBC1D7). Of these components, Tsc2 is recruited to the lysosome in response to the removal of growth factors or amino acids. In contrast, mTORC1 also translocates to the lysosome by the action of the Rag GTPase and the Ragulator (Jewell et al. 2013). Rag is a heterodimeric GTPase, and Ragulator is the GEF and lysosomal anchor for Rag. Rag GTPases consist of four similar mammalian homologues (RagA, RagB, RagC, and RagD). The recruitment of mTORC1 to the lysosome is promoted by GTP-bound RagA/RagB and GDP-bound RagC/RagD, whereas it is inhibited by GDP-bound RagA/RagB and GTP-bound RagC/RagD. Ragulator exhibits GEF activity toward RagA/RagB. Thus, Ragulator anchors Rag heterodimers with mTORC1 to the lysosome. mTORC1 localization to the lysosome is thought to enhance its activity by bringing it close to the membrane-associated Rheb. Rheb has also been demonstrated to localize to other organelles including mitochondria and peroxisome (Heard et al. 2014).

Physiological Function of Rheb

Rheb is a crucial regulator of mTORC1. Because mTORC1 is one of the major key signaling hub protein complexes, Rheb affects many aspects of cellular functions, most notably cell proliferation. Studies using knockout mice have shown that Rheb is involved in the development of the cardiovascular system and central nervous system. Studies on Rheb knockout mice have revealed that homozygous Rheb mutant mice show embryonic lethality (Goorden et al. 2011; Zou et al. 2011). Mouse embryonic fibroblasts (MEFs) obtained from Rheb −/− mice show impaired mTORC1 activity and consequently decreased phosphorylation of S6K and 4E-BP1, which are substrate proteins of mTORC1 (Goorden et al. 2011). The decreased phosphorylation of S6K and 4E-BP1 impedes protein translation, thus resulting in impaired cell proliferation, survival, and metabolism (Fig. 2a). These cellular defects could cause embryonic lethality.

Histological analysis of Rheb −/− embryos has indicated that heart development is impaired (Table 1). In particular, pericardial hemorrhages and thinning of the ventricular walls have been observed. A failure in heart development may lead to circulatory failure and hypoxia in different organs, thus causing embryonic lethality (Goorden et al. 2011). Cardiomyocyte-specific conditional Rheb knockout mice have been generated to investigate Rheb function in heart development (Table 1). These conditional knockout mice die by postnatal days 11 to 16. Knockout mice show abnormal heart growth and retarded cardiomyocyte size at postnatal days 9 and 11. In addition, malignant ventricular arrhythmias occur in these mice (Cao et al. 2013; Tamai et al. 2013). The impaired heart development and heart function in Rheb mutant mice is explained primarily by decreased mTORC1 activity. The phosphorylation of S6K and 4E-BP1 is dramatically reduced in cardiomyocytes from Rheb mutant mice, thus resulting in impaired energy metabolism in cardiomyocytes (Cao et al. 2013; Tamai et al. 2013). Finally, Rheb deletion results in increased cardiomyocyte apoptosis (Tamai et al. 2013).
RHEB, Table 1

Summary of Rheb knockout mouse studies

 

Abbreviation

Tissue

Promoter

Phenotype

References

Knockout

Rheb−/−

All

Actin-Cre

Embryonic lethality by E12, probably due to circulatory failure

Goorden et al. (2011), Zou et al. (2011)

Conditional knockout

Rhebflox/flox; Nes-Cre

Neural progenitor cells

Nes-Cre

Decreased brain weight and cortical thickness and hypomyelination. Animals survive up to 6 weeks after birth

Zou et al. (2011)

Rhebflox/flox; αMHC-Cre

Cardiac

αMHC-Cre

Animals die by postnatal day 10. Hypotrophy, retarded cardiomyocyte growth

Cao et al. (2013), Tamai et al. (2013)

T-Rheb−/−

CD4+ T-cells

Cd4-Cre

Fail to produce TH1 and TH17 cells

Heard et al. (2014)

Rhebflox/−; Vasa-Cre

Germ cells

Vasa-Cre

Male sterility and no effect on female fertility

Heard et al. (2014)

Rheb1flox/flox;

Olig1-Cre or Olig2-Cre

Oligodendrocyte precursor cells

Olig1-Cre or Olig2-Cre

Hypomyelination, reduced oligodendrogenesis

Zou et al. (2014)

Inducible knockout

Rheb1flox/−; Cagg-CreEsr1

All

CAGG-Cre

Lethality by approximately 18 days after tamoxifen injection. Normal L-LTP and spatial memory on day 14 after tamoxifen injection

Goorden et al. (2015)

Mice generated to study Rheb function are listed, along with a brief description of their phenotypes

Rheb is also involved in the myelination of neurons and neural development. Neural progenitor-specific Rheb knockout mice survive up to postnatal week 6 (Table 1). Histological analysis has revealed that the gross morphology of the brain is preserved at P5. However, by P5–P9, the brain weight of Rheb1 knockout mice is less than the weight of the WT brain, and this difference becomes more pronounced over the course of subsequent development (Zou et al. 2011). The cortical thickness of the Rheb knockout mice is reduced before the mice reach 4 weeks of age. Nissl and NeuN staining indicated that the number of cortical neurons in Rheb knockout brain is almost equivalent to that in WT brains. In contrast, Rheb knockout mice show prominent hypomyelination. Western blot analysis has revealed a decrease in myelin proteins including myelin basic protein (MBP) in 4-week old brains. Immunohistochemical analysis has also revealed a similar reduction in the cortex, hippocampus, and cerebellum (Zou et al. 2011). Thus, the hypomyelination appears to be due to lack of mature oligodendrocytes. Similarly, oligodendrocyte precursor-specific Rheb knockout mice show impaired myelination in the brain (Zou et al. 2014). Oligodendrocyte precursors in Rheb mutant mice are impaired in cell cycle exit, and oligodendrogenesis and myelination are reduced in the brains of the Rheb mutant mice. The Rheb-mTORC1 pathway may be required for oligodendrocyte maturation.

Other neuronal development is supported by Rheb signaling through the activation of mTORC1. Rheb activity is required for the establishment of neuronal polarity. The knockdown of Rheb results in poor axonal differentiation, whereas the overexpression of Rheb induces the formation of multiple axons (Li et al. 2008). The Rheb-mediated surplus axon formation is blocked by knockdown of Rap1B, thus suggesting that the effect of the Rheb/mTORC1 pathway in axonal formation might depend on Rap1B. In addition, impaired axonal formation by knockdown of Rheb is restored by the expression of a constitutively active Rap1B mutant, thus indicating that the Rheb/mTORC1 pathway acts upstream of Rap1B in neuronal polarization (Li et al. 2008). The Rheb/mTORC1 signaling pathway also regulates axonal elongation. Pharmacological inhibition of Rheb activity suppresses the local translation of TC10 and Par3 in the growth cone (Gracias et al. 2014). TC10 local translation is required for membrane expansion in the growth cone and axonal elongation. Rapamycin treatment also inhibits TC10-mediated axonal elongation, thus increasing the possibility that the Rheb/mTORC1 pathway is required in axonal elongation (Gracias et al. 2014).

In contrast, mTORC-independent Rheb activity contributes to neuronal functions. Synaptic morphogenesis and synapse function are mediated by Rheb activity. The expression level of Rheb correlates with synaptic growth and physiological function in Drosophila larval neuromuscular junctions. Rapamycin treatment does not inhibit synapse growth mediated by Rheb overexpression. Instead of mTORC1 signaling, bone morphogenetic protein (BMP) is required for Rheb-induced synaptic growth. In addition, Rheb is involved in proper spine morphogenesis in rodents. Tsc2 +/− mice and rats (Eker rat) show altered spine morphology. In Tsc2 +/− neurons, dendritic spines are thinner and longer, similarly to filopodia, and excitatory synapses are directly formed on the dendritic shafts (Yasuda et al. 2014). Poor Tsc1/Tsc2 activity results in the activation of Rheb, thus leading to the increase of free syntenin protein. Syntenin is a PDZ domain-containing adaptor protein. Increased syntenin protein repels CASK away from syndecan-2 in dendritic spines, thus resulting in aberrant spine formation. Instead, increased syntenin causes shaft synapse morphogenesis through its interaction with dendritic ephrinB3 (Sugiura et al. 2015). The altered form of excitatory synapses may cause neuronal dysfunction and neurodevelopmental disorders, such as autism and mental retardation and/or epilepsy.

Rheb functions in other cell systems have been investigated in conditional knockout mice. CD4+-T cell-specific Rheb knockout results in impaired differentiation to TH1 and TH17 cells. Knockout mice harbor only TH2 cells, and they are resistant to the development of classical experimental autoimmune encephalomyelitis (Heard et al. 2014). Moreover, analysis of germline cell-specific Rheb knockout mice has revealed decreased sperm counts and abnormal sperm morphology, causing sterility, in male knockout mice. However, female knockout mice show no effects in the ovaries and they remain fertile (Heard et al. 2014). Furthermore, investigation of tamoxifen-inducible knockout mice has revealed that the loss of Rheb is lethal in adult mice, and the mice have a median survival time of 18 days after initiating tamoxifen injection (Goorden et al. 2015). These results demonstrate that Rheb is also essential for survival in adult life. The knockout mouse strains and their phenotypes described here are summarized in Table 1.

Rheb-Related Disorders

Because mTORC1-mediated S6K and 4E-BP1 phosphorylation are highly involved in cell proliferation and survival, Rheb activity in cancer cells has been well studied. The expression of Rheb is elevated in several tumor cell lines and in human carcinomas. The chromosome harboring the Rheb gene is frequently amplified in human cancers, including liver, lung, and bladder carcinomas. A high level of Rheb mRNA has been statistically associated with breast cancer progression. In addition, the mutations (Y35N) in the Rheb gene are frequently identified in human renal cell carcinoma and several other cancers. Because Tyr35 is thought to be required for sensitivity to Tsc2 GAP, the Y35N mutation in Rheb protein confers resistance to the GAP activity of Tsc2, thus leading to the hyperactivation of mTORC1 (Ghosh et al. 2015). Other representative point mutations of Rheb are shown in Fig. 1.

Mutations of Tsc1/Tsc2 genes also cause the activation of Rheb, resulting in the development of TSC. In TSC patients, benign tumors (hamartoma) are observed in the brain, kidney, lung, and heart. Because the phosphorylation of S6K and 4E-BP1 promotes the initiation of protein translation and protein synthesis, this signaling cascade upregulates cell proliferation, growth, and survival. In contrast, refractory epilepsy, intellectual disability, and/or autism frequently occur in TSC patients. As stated above, cultured neurons from Tsc2 +/− rats and mice show altered synapse formation, which is recovered by the expression of dominant negative Rheb. Furthermore, because the mTORC1 inhibitor rapamycin does not restore impaired synapse formation in Tsc2 +/− neurons, cognitive symptoms in TSC patients may be caused by Rheb activation rather than by mTORC1 activation (Yasuda et al. 2014).

Summary

Rheb is a member of the Ras family of small G proteins. Rheb has a specific conformation that allows it to maintain its GTP-bound active form. Active Rheb directly interacts with mTOR and activates the mTORC1 signaling cascade. Rheb-mediated mTORC1 regulation is involved in cell proliferation, survival, and metabolism through the phosphorylation of S6K and 4E-BP1. The main regulator, a GAP for Rheb, is the Tsc1/Tsc2 complex. Tsc1 and Tsc2 are the genes responsible for tuberous sclerosis. Thus, the function of Rheb may be involved in the pathogenesis of tuberous sclerosis. Studies on Rheb knockout mice have revealed that Rheb function is necessary for cardiovascular development. Conventional Rheb knockout mice show embryonic lethality, and cardiomyocyte-specific Rheb knockout mice survive until only approximately 2 weeks after birth. Studies on knockout mice have also shown that Rheb is required for myelination and neuronal development. Neural precursor-specific Rheb knockout mice show impaired brain development, and oligodendrocyte precursor cells of conditional knockout mice show hypomyelination. In addition, Rheb is required for proper synapse formation and spine morphology. Overall, Rheb is a key regulator of mTORC1, and Rheb controls various cellular functions through mTORC1 activity. The development of adequate Rheb inhibitors may be useful for the treatment of tuberous sclerosis.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Tadayuki Shimada
    • 1
  • Hiroko Sugiura
    • 1
  • Kanato Yamagata
    • 1
    • 2
  1. 1.Synaptic Plasticity ProjectTokyo Metropolitan Institute of Medical ScienceSetagayaJapan
  2. 2.Department of PharmacologyShukutoku UniversityChibaJapan