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FLASH GENE

Symbol

RHEB

contributors: mct/pgu - updated : 04-09-2018

HGNC name	Ras homolog enriched in brain
HGNC id	10011

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Mus musculus Adult   vessel       highly Digestive salivary gland       highly Hearing/Equilibrium ear       highly Nervous brain hindbrain medulla oblongata     Mus musculus Adult   brain limbic system hippocampus     Mus musculus Adult   brain forebrain cerebral cortex     Mus musculus Adult   brain hindbrain cerebellum     Mus musculus Adult Olfactory (smell) olfactory bulb         Mus musculus Adult Reproductive female system placenta     highly Skin/Tegument skin       highly Urinary bladder         Mus musculus Adult

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly Muscular striatum skeletal     Mus musculus Fetal Muscular striatum cardiac

cells

System Cell Pubmed Species Stage Rna symbol not specific fibroblast

cell lineage
cell lines	breast carcinoma
fluid/secretion

at STAGE

physiological period

fetal

Text

brain

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	five repeats of the RAS-related GTP-binding region
	targeted to endomembranes via its C-terminal CAAX (C=cysteine, A=aliphatic, X=terminal amino acid) motif, a substrate for posttranslational modification by a farnesyl isoprenoid

conjugated

LipoP , Other

mono polymer

complex

HOMOLOGY

interspecies

homolog to murine Rheb (98.9 pc)

intraspecies

homolog to Ras (enriched in brain)

Homologene

FAMILY	Ras-oncogene superfamily member
	small GTPase superfamily
	Rheb family

CATEGORY

immunity/defense , protooncogene , signaling growth factor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,lysosome
	intracellular,cytoplasm,cytosolic
text	lipid-anchorto the cytoplasmic side
	RHEB and RHEBL1 localize primarily to the endoplasmic reticulum and Golgi apparatus
	RHEB is activated at the Golgi from where it will travel to lysosomes

basic FUNCTION	exhibiting intrinsic GTPase activity
	may control growth
	promoting mTOR-dependent S6 kinase activation in a rapamycin- and farnesylation-dependent manner
	stimulating phosphorylation of 4EBP1
	playing an important role in cellular responses to energy limitation and nutrient starvation
	may also control BCL2-dependent apoptosis and calcineurin-dependent transcription through FKBP8
	activating FRAP1 by antagonizing its endogenous inhibitor, FKBP8
	playing a vital role in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway
	directly activating MTOR, in a farnesylation-dependent manner
	critical for embryonic survival and MTOR signaling
	essential for MTOR signaling and myelination in the brain, suggesting that MTOR signaling plays a role in selective cellular adaptations, rather than general cellular viability
	negatively regulates myoblast differentiation through suppression of IRS1 and inhibition of AKT activation
	function of RPTOR and RHEB in myogenesis is mediated by IRS1
	essential role of RHEB in diverse aspects of spermatogenesis, suggesting the existence of functionally redundant factors that can compensate for RHEB deficiency within oocytes
	oligodendrocyte progenitor cells (OPCs) -intrinsic MTOR activity mediated by RHEB is critical for differentiation of OPCs to mature oligodendrocytes, but that mature oligodendrocytes do not require RHEB to make myelin or maintain it in the adult brain
	possible role of RHEB and RHEBL1 in regulating de novo pyrimidine nucleotide synthesis
	expression pattern of RHEB suggests that it likely plays a ubiquitous role in the development of the early embryo with more tissue-specific roles in later development
	RHEB induces a distinct gene expression signature that maintained the innate chondrogenic properties over a long period
	is critical for macrophage production and phagocytosis and executes these activities possibly via MTOR-dependent pathway
	distinct roles of RHEB and RPTOR in activating MTOR for the self-renewal of hematopoietic stem cells

CELLULAR PROCESS	cell life, proliferation/growth
	protein, translation regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

long term, activity dependent, neuronal response

a component

spliceosome

INTERACTION

DNA

RNA

small molecule	nucleotide,
	GTP

protein	binding tuberous sclerosis complex 2 (TSC2)
	interacting with FKBP8
	positive upstream regulator of the target of rapamycin (TOR) complex 1 in mammalian cells and can bind directly to MTOR
	direct regulation of RHEB by MAPKAPK5 integrates a stress pathway with the MTOR pathway in response to energy depletion
	activation of MTOR is regulated by a small G-protein, RHEB
	IRS1 is a critical mediator of the myogenic functions of raptor and RHEB
	RHEB and EFNA5 come together at the lysosome to activate MTOR
	RHEB interacts with BACE1 and degrades it through proteasomal and lysosomal pathways
	RHEB proteins binds to CAD protein (RHEB and RHEBL1 binds CAD in a GTP- and effector domain-dependent manner)
	RHEB and RHEBL1 are unique members of the Ras superfamily and play central roles in regulating protein synthesis and cell growth by activating MTOR
	PDZ protein SDCBP preferentially binds to the GDP-bound form of RHEB
	RASSF1 inhibits the ability of RHEB to suppress autophagy and enhance cell growth, and RHEB may complex with RASSF1 to coordinate Hippo and MTOR signaling
	RHEB interaction with BRAF is crucial for inhibiting RAF/MEK/ERK signaling
	function of RHEB to activate MTOR signaling
	MTOR activation by RHEB and inhibition by AKT1S1

cell & other

REGULATION

activated by

TSC2/TSC1 complex, (its GTPase activity is activated by the complex of TSC1 and TSC2 whose mutations cause tuberous sclerosis complex (TSC)

inhibited by

a farnesyl transferase inhibitor

Other	post-translationally modified by the farnesyl lipid, for attachment to membranes
	methylated and prenylated

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   amplification     in human prostate cancers constitutional     --low   inhibited the monocyte-to-macrophage differentiation process constitutional     --low   RHEB levels are down-regulated in the Alzheimer disease brain, which is consistent with an increased BACE1 expression

Susceptibility

Variant & Polymorphism

Candidate gene	for holoprosencephaly type 3 and/or sacral agenesis
Marker
Therapy target

ANIMAL & CELL MODELS

absolute number of macrophages decreased in the bone marrow (BM) of Rheb1-deficient mice