RHEB

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RHEB
Protein RHEB PDB 1xtq.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases RHEB , RHEB2, Ras homolog enriched in brain, Ras homolog, mTORC1 binding
External IDs OMIM: 601293 MGI: 97912 HomoloGene: 123916 GeneCards: RHEB
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005614

NM_053075

RefSeq (protein)

NP_005605

NP_444305

Location (UCSC) Chr 7: 151.47 – 151.52 Mb Chr 5: 25.01 – 25.05 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle. [5]

Contents

RHEB is a recently discovered member of the Ras superfamily. Being a relative of Ras, the overexpression of RHEB can be seen in multiple human carcinomas. [6] For this reason, ways to inhibit RHEB to control the mTOR pathway are studied as possible treatments for uncontrollable tumor cell growth in several diseases, especially in tuberous sclerosis. [7]

Structure

GDP bound to RHEB: GDP is in orange, GTPase region is in green, and hypervariable region in pink. GDP bound Rheb.png
GDP bound to RHEB: GDP is in orange, GTPase region is in green, and hypervariable region in pink.
GTP bound to RHEB: GTP is in orange, GTPase region is in green, and hypervariable region in pink. GTP bound Rheb.png
GTP bound to RHEB: GTP is in orange, GTPase region is in green, and hypervariable region in pink.

Rheb is a 21  kDa protein monomer composed of 184 amino acids. [5] The first 169 amino acids by the N-terminus make up the GTPase domain, and the remaining amino acids are part of a hypervariable region ending at the C-terminus in a CAAX motif (C – cysteine, A – aliphatic amino acid, X – C-terminus amino acid). [8]

The protein is a lipid-anchored, cell-membrane protein with five repeats of the RAS-related GTP-binding region. [5] Also present are “switch” regions, I and II, which undergo conformational changes when shuttling between GTP-bound(activated) and GDP-bound(inactive) forms. [8]

RHEB is expressed by the RHEB gene in humans. [9] Three pseudogenes have been mapped, two on chromosome 10 and one on chromosome 22. [5]

Function

Activation of mTORC1

RHEB is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. [10] Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a serine/threonine kinase whose activation leads to phosphorylation cascades within the cell that lead to cell growth and proliferation. [11] RHEB localizes at the lysosome to activate mTORC1 and Rag7 proteins localize mTORC1 to the lysosome and the Ragulator-Rag complex, allowing RHEB to activate the protein. [12] RHEB acts as an activator for mTORC1 in its GTP-bound form, therefore GTP-bound RHEB activates cell growth and proliferation within the cell.

mTORC1 independent functions

RHEB can serve as a regulator, for other proteins independent from mTORC1. For example, RHEB is an activator for nucleotide synthesis by binding carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), an enzyme required for de novo pyrimidine nucleotide synthesis. [13] An increased nucleotide pool within the cell can lead to increased cell proliferation. mTORC1 is also a regulator for CAD, so both RHEB and mTORC1 are involved with the control of nucleotide level within the cell. [13] 5' adenosine-monophosphate-activated protein kinase (AMPK) has also been found to be an effector for RHEB. [14] AMPK is a protein kinase that begins a phosphorylation cascade leading to autophagy. In rat studies, RHEB activates AMPK. [14] RHEB has also been found to interact with effectors upstream in the mTOR pathway. Phospholipase D1 (PLD1) is upstream in the mTOR pathway and serves as a positive effector for mTORC1. [15]

Other functions

RHEB may be involved in neural plasticity. This function is novel and not typically associated with the Ras proteins. Deficiency of RHEB in the forebrain of mice embryos is associated with decreased myelinization due to a decrease of mature oligodendrocytes. [8]

In studies of RHEB knockout mice, it was shown through hematoxylin-eosin staining that heart development is highly impaired. The cardiac myocytes do not sufficiently grow in size, indicating that RHEB mTOR function is required. This suggested that RHEB and the activation of the mTOR pathway is a necessity for proper cardiac development in mice embryos. [16]

RHEB switch II (blue) has a less alpha-helical structure as compared to RAS switch II. RHEB SWITCH II.png
RHEB switch II (blue) has a less alpha-helical structure as compared to RAS switch II.

Differences from Ras superfamily

RHEB functions differently compared to other proteins in the Ras superfamily. [8] Similar to those in the Ras superfamily, the protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity. However, unlike those in the Ras superfamily, conformational change when shuttling between forms only affects switch I, while switch II remains relatively stable, due to difference in secondary structure. Ras switch II forms a long α-helical structure between shuttling, while RHEB switch II adopts a more atypical conformation allowing for novel functions. [17] Such a conformation causes a decreased intrinsic rate of GTP hydrolysis as compared to RAS due to the catalytic Asp65 in the switch II region of RHEB being blocked from the active site. [11]

Regulation

GTP hydrolysis activity of RHEB is intrinsically slow and the GTP-bound form is more common, thus RHEB is more likely active than not active within the cell. [11] Its activity is strongly regulated within the cell by tumor-suppressant proteins that form the TSC complex. Specifically, the TSC2 subunit, tuberin of the complex interacts with and inhibits RHEB to regulate the protein. Tuberin stimulates RHEB to hydrolyze GTP, thus inactivating it. [18]

Tuberous sclerosis

Tuberous sclerosis is an autosomal dominant disease in which the genes required to express the tumor-suppressant proteins that form the TSC complex is mutated or missing, so the TSC complex is unable to function properly. [19] This could lead to the disregulation of many signalling proteins and effectors within the cell, including RHEB. Unregulated activity of RHEB can lead to uncontrollable cell growth and cell division which could ultimately lead to formation of tumors. [8]

Interactions

RHEB has been shown to interact with:

Related Research Articles

mTOR Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

<span class="mw-page-title-main">TSC1</span>

Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the TSC1 gene.

<span class="mw-page-title-main">Folliculin</span> Protein-coding gene

The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.

<span class="mw-page-title-main">TSC2</span> Mammalian protein found in Homo sapiens

Tuberous sclerosis complex 2 (TSC2), also known as tuberin, is a protein that in humans is encoded by the TSC2 gene.

<span class="mw-page-title-main">RAS p21 protein activator 1</span> Protein-coding gene in the species Homo sapiens

RAS p21 protein activator 1 or RasGAP, also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:

<span class="mw-page-title-main">RAP1A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-1A is a protein that in humans is encoded by the RAP1A gene.

<span class="mw-page-title-main">RPS6KA1</span> Enzyme

Ribosomal protein S6 kinase alpha-1 is an enzyme that in humans is encoded by the RPS6KA1 gene.

<span class="mw-page-title-main">P70-S6 Kinase 1</span> Protein-coding gene in the species Homo sapiens

Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase, is an enzyme that in humans is encoded by the RPS6KB1 gene. It is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway. As the name suggests, its target substrate is the S6 ribosomal protein. Phosphorylation of S6 induces protein synthesis at the ribosome.

<span class="mw-page-title-main">Protein kinase, AMP-activated, alpha 1</span> Protein-coding gene in the species Homo sapiens

5'-AMP-activated protein kinase catalytic subunit alpha-1 is an enzyme that in humans is encoded by the PRKAA1 gene.

<span class="mw-page-title-main">RALA</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7. This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers.

<span class="mw-page-title-main">RAP2A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-2a is a protein that in humans is encoded by the RAP2A gene. RAP2A is a member of the Ras-related protein family.

<span class="mw-page-title-main">RPTOR</span> Protein-coding gene in humans

Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.

<span class="mw-page-title-main">DDIT4</span> Protein-coding gene in the species Homo sapiens

DNA-damage-inducible transcript 4 (DDIT4) protein also known as protein regulated in development and DNA damage response 1 (REDD1) is a protein that in humans is encoded by the DDIT4 gene.

<span class="mw-page-title-main">MRAS</span> Protein

Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the MRAS gene on chromosome 3. It is ubiquitously expressed in many tissues and cell types. This protein functions as a signal transducer for a wide variety of signaling pathways, including those promoting neural and bone formation as well as tumor growth. The MRAS gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Dedicator of cytokinesis protein 7</span> Protein found in humans

Dedicator of cytokinesis protein (Dock7) is a large protein encoded in the human by the DOCK7 gene, involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock7 activates isoforms of the small G protein Rac.

Kun-Liang Guan, is a Chinese and American biochemist. He won the MacArthur Award in 1998.

Tuberous sclerosis proteins 1 and 2, also known as TSC1 (hamartin) and TSC2 (tuberin), form a protein-complex. The encoding two genes are TSC1 and TSC2. The complex is known as a tumor suppressor. Mutations in these genes can cause tuberous sclerosis complex. Depending on the grade of the disease, intellectual disability, epilepsy and tumors of the skin, retina, heart, kidney and the central nervous system can be symptoms.

mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs used to treat several human diseases, including cancer, autoimmune diseases, and neurodegeneration. They function by inhibiting the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

mTORC1 Protein complex

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.

<span class="mw-page-title-main">Ragulator-Rag complex</span> Aspect of cell metabolism

The Ragulator-Rag complex is a regulator of lysosomal signalling and trafficking in eukaryotic cells, which plays an important role in regulating cell metabolism and growth in response to nutrient availability in the cell. The Ragulator-Rag Complex is composed of five LAMTOR subunits, which work to regulate MAPK and mTOR complex 1. The LAMTOR subunits form a complex with Rag GTPase and v-ATPase, which sits on the cell’s lysosomes and detects the availability of amino acids. If the Ragulator complex receives signals for low amino acid count, it will start the process of catabolizing the cell. If there is an abundance of amino acids available to the cell, the Ragulator complex will signal that the cell can continue to grow. Ragulator proteins come in two different forms: Rag A/Rag B and Rag C/Rag D. These interact to form heterodimers with one another.

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Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.