Human Disease Model Report: insulin pathway effects, RHEB-related

General Information

Name

insulin pathway effects, RHEB-related

FlyBase ID

FBhh0000485

Disease Ontology Term

glucose metabolism disease

Parent Disease

OMIM

Overview

This report describes a potential fly model of type 2 diabetes or related disorders using loss-of-function mutations of Dmel\Rheb, which is postulated to act in the Drosophila insulin pathway. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for the Rheb gene.

In human, there are two genes orthologous to Dmel\Rheb, RHEB and RHEBL1; RHEB encodes a lipid-anchored GTPase that has been shown to have a role in the insulin/TOR/S6K signaling pathway. The human gene Hsap\RHEB has been introduced into flies; heterologous rescue has not been tested.

Severe loss-of-function mutations of Dmel\Rheb are homozygous lethal in the larval or pupal stages. Flies with partial loss-of-function alleles exhibit significantly reduced body weight; some alleles exhibit higher total lipid content and impairment in retinal function. Genetic and physical interactions have been described for Dmel\Rheb; see below and in the Rheb gene report.

[updated Jan. 2017 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: insulin pathway effects, RHEB-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

RHEB is a member of the GTPase superfamily and encodes a lipid-anchored, cell membrane protein with five repeats of the RAS-related GTP-binding region. It has been shown to have a role in the insulin/TOR/S6K signaling pathway. [Gene Cards, RHEB; 2017.01.27]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): RHEB
Gene2Function (human gene): RHEBL1
Gene Cards: RHEB
Gene Cards: RHEBL1
MedlinePlus (gene): RHEBL1
MedlinePlus (gene): RHEB
MARRVEL (human gene): RHEB
MARRVEL (human gene): RHEBL1
NCBI (Entrez) gene: RHEB; Ras homolog, mTORC1 binding
NCBI (Entrez) gene: RHEBL1; RHEB like 1

Disease synonyms

Related Diseases

Related human health report(s)

diabetes mellitus, noninsulin-dependent (type 2) (fly models overview)

Ortholog Information

Human gene(s) in FlyBase

Hsap\RHEB

Human gene (HGNC)

Symbol / Name

RHEBL1; RHEB like 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Rheb

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one (2 human to 1 Drosophila): the second orthologous gene in human is RHEB.

Human gene (HGNC)

Symbol / Name

RHEB; Ras homolog, mTORC1 binding

D. melanogaster ortholog (based on DIOPT)

Dmel\Rheb

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one (2 human to 1 Drosophila): the second orthologous gene in human is RHEBL1.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Rheb

Gene Snapshot

Ras homolog enriched in brain (Rheb) encodes a Ras homolog that is the target of the product of gig. It activates the protein kinase encoded by mTor, leading to enlarged cell size. [Date last reviewed: 2018-11-08]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human RHEB; moderate-scoring ortholog of RHEBL1 (1 Drosophila to 2 human). Dmel\Rheb shares 64% identity and 81% similarity with RHEB; it shares 55% identity and 74% similarity with RHEBL1.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (88 groups)

Rheb

protein-protein

Interacting group

Assay

References

Rheb - 14-3-3ε

anti tag coimmunoprecipitation, anti tag western blot, Identification by mass spectrometry, pull down, western blot

(Le et al., 2016, Vinayagam et al., 2016)

Rheb - 14-3-3ζ

anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot

(Le et al., 2016)

Rheb - Act5C

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Act57B

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Actn

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - AGO2

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - alt

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - ATPsynβ

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - bif

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CCT1

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, Identification by mass spectrometry

(Kim and Choi, 2019, Vinayagam et al., 2016)

Rheb - CCT4

anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot, pull down

(Kim and Choi, 2019)

Rheb - CCT5

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CCT7

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CG1416

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CG5516

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CG7054

bimolecular fluorescence complementation, fluorescence microscopy

(Känel et al., 2022)

Rheb - CG11417

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CG12301

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CG13096

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CG13775

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - CG32708

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Cln7

anti tag coimmunoprecipitation, anti tag western blot

(Connolly et al., 2019)

Rheb - cpa

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - cpb

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Dp1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Droj2

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - eIF2α

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - eIF2γ

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - eIF3a

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - eIF3i

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - eIF3l

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - eIF3m

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - eIF4A

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - FASN1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Fib

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - foxo

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - gig

enzymatic study, autoradiography, anti tag coimmunoprecipitation, peptide massfingerprinting

(Glatter et al., 2011, Zhang et al., 2003)

Rheb - Hsc70-3

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Hsc70-5

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Imp

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Ipo9

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Iswi

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - l(2)09851

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - mask

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Nap1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Noc2

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - nonA

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Ns3

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Nsun2

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Pi3K21B

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - pths

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - qkr58E-3

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Ref1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - rin

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Rm62

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL6

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL7A

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL8

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL9

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL10

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL10Ab

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL13

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL14

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL17

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL18

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL27

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL30

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL35A

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpL36

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpS5a

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpS6

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpS7

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpS14a

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - RpS23

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Rpt1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Rpt3

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Rtf1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - sau

anti tag coimmunoprecipitation, western blot

(Frappaolo et al., 2022)

Rheb - sqd

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - sqh

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Tctp

anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot

(Frappaolo et al., 2022, Le et al., 2016, Hsu et al., 2007)

Rheb - TER94

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Tsc1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Glatter et al., 2011)

Rheb - tyf

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - vig2

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - ZC3H18

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - zip

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Rheb - Zn72D

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Alleles Reported to Model Human Disease (Disease Ontology) (8 alleles)

Rheb

Models Based on Experimental Evidence ( 5 )

Allele

Disease

Evidence

References

Rheb^2D1

model of type 2 diabetes mellitus

CEA with Rheb^7A1

(Murillo-Maldonado et al., 2011)

CEA with Rheb^44.1

(Murillo-Maldonado et al., 2011)

Rheb^44.1

model of type 2 diabetes mellitus

CEA with Rheb^7A1

(Murillo-Maldonado et al., 2011)

CEA with Rheb^2D1

(Murillo-Maldonado et al., 2011)

Rheb^7A1

model of type 2 diabetes mellitus

CEA

(Murillo-Maldonado et al., 2011)

CEA with Rheb^2D1

(Murillo-Maldonado et al., 2011)

CEA with Rheb^44.1

(Murillo-Maldonado et al., 2011)

Rheb^{EP50.084-loxP}

model of disease of metabolism

CEA

(Devilliers et al., 2021)

Rheb^UAS.cPa

model of tuberous sclerosis

CEA

(Dimitroff et al., 2012)

Modifiers Based on Experimental Evidence ( 3 )

Allele

Disease

Interaction

References

Rheb^HMS00923

exacerbates syndrome

modeled by RpS23^R67K

(Recasens-Alvarez et al., 2021)

Rheb^1.1.UAS

exacerbates tauopathy

modeled by Hsap\MAPT^{S202A.T205A.UAS}

(Steinhilb et al., 2007)

modeled by Hsap\MAPT^{T231A.S235A.UAS}

(Steinhilb et al., 2007)

modeled by Hsap\MAPT^{S396A.S404A.UAS}

(Steinhilb et al., 2007)

ameliorates tauopathy

modeled by Hsap\MAPT^UAS.cWa

(Steinhilb et al., 2007)

Rheb^lexAop.cRa

ameliorates high grade glioma

modeled by btl::Egfr^λ.UAS

(Jarabo et al., 2022)

modeled by Pi3K92E^{UAS.Tag:MYC,Tag:PM(hKRAS)}, btl::Egfr^λ.UAS

(Jarabo et al., 2021)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\RHEB^UAS.Tag:HA

M{UAS-hRHEB.HA}

y¹ w^*; M{UAS-hRHEB.HA}ZH-86Fb

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Rheb^{lexAop.HMS00923}

P{lexAop-HMS00923}

Rheb^HMJ21217

P{TRiP.HMJ21217}

y¹ v¹; P{TRiP.HMJ21217}attP40/CyO

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00923}attP2

Rheb^NIG.1081R

P{NIG.1081R}

P{NIG.1081R}2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Rheb^AV4

loss of function allele

P-element activity

y¹ w^*; P{Mae-UAS.6.11}Rheb^AV4/TM6B, Tb¹

Rheb^{EP50.084-loxP}

cre recombinase

Rheb^44.1

Delta2-3 transposase

Rheb^2D1

ethyl methanesulfonate

Rheb^7A1

ethyl methanesulfonate

References (4)

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