Human Disease Model Report: cancer, multiple, BRAF-related

General Information

Name

cancer, multiple, BRAF-related

FlyBase ID

FBhh0000960

Disease Ontology Term

cancer

Parent Disease

OMIM

Overview

The RAF genes encode serine/threonine-protein kinases that act as links between the membrane-associated RAS GTPases and the MAPK/ERK cascade. The RAS-RAF-MEK-ERK pathway impacts proliferation, differentiation, apoptosis, and oncogenic transformation; as might be expected, many of the genes in the pathway are implicated in the development of cancer. This report describes a fly model that uses a disease-implicated variant of the human BRAF gene. There are two additional RAF genes in human, ARAF and RAF1. In Drosophila, there is a single orthologous gene, Dmel\Raf, for which classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Several UAS constructs of the human Hsap\BRAF carrying a specific disease-implicated variant have been introduced into flies. Variant(s) implicated in human disease tested (as transgenic human gene, BRAF): the V600E variant form has been introduced into flies. The V600E variant constitutively activates the kinase and has been found in many forms of cancer (see MIM:164757).

This disease model has been designed to facilitate assessment of pharmaceutical treatment options. The GAL4-UAS system is used to express the BRAF V600E variant form in a variety of tissues; useful and easily quantitated phenotypes include lethality, semi-lethality and a rough eye phenotype. Single drugs as well as a combined treatment have been assessed.

An analogous change introduced into the Dmel\Raf gene has also been studied. Variant(s) implicated in human disease (analogous mutation in fly gene): A572E in the fly Raf gene (corresponds to V600E in the human BRAF gene).

See also the human disease model report 'cancer, multiple, RAF1-related' (FBhh0000558). Hsap\BRAF has also been used in a fly model of Noonan syndrome 7 (FBhh0001344).

[updated May 2021 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: cancer, multiple, BRAF-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

Variation in the kinase domain of BRAF have been associated with various cancers. The most common BRAF variant, V600E, constitutively activates the kinase, and causes cell proliferation in the absence of growth factors that would normally be required. The V600E variant is detected in approximately 50% of melanomas. [Medgen, Vemurafenib response; 893721]

(FlyBase Curators, 2013-)

External links

COSMIC gene: BRAF
Gene2Function (human gene): BRAF
Gene Cards: BRAF
MedlinePlus (gene): BRAF
KEGG Disease Pathways: Pathways in Cancer
MARRVEL (human gene): BRAF
NCBI (Entrez) gene: BRAF; B-Raf proto-oncogene, serine/threonine kinase

Disease synonyms

Related Diseases

Related human health report(s)

cancer, multiple, RAF1-related

Ortholog Information

Human gene(s) in FlyBase

Hsap\BRAF

Human gene (HGNC)

Symbol / Name

BRAF; B-Raf proto-oncogene, serine/threonine kinase

D. melanogaster ortholog (based on DIOPT)

Dmel\Raf

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila. The three human genes are BRAF, RAF1, and ARAF.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Raf

Gene Snapshot

Raf oncogene (Raf) encodes a serine-threonine protein kinase that acts downstream of the product of Ras85D. It activates the MEK/ERK pathway to regulate cell proliferation, differentiation and survival downstream of receptor tyrosine kinases such as those encoded by tor, Egfr, and sev. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human BRAF, ARAF, RAF1 (1 Drosophila to 3 human). Dmel\Raf shares 43-47% identity and 56-60% similarity with the human genes.

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 (90 groups)

Raf

protein-protein

Interacting group

Assay

References

Raf - 14-3-3ε

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - 14-3-3ζ

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Act42A

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Aldh

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Apl

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Arc1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - AspRS-m

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - ave

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

(Maisonneuve et al., 2024)

Raf - BCAS2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - βCOP

anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting

(Friedman et al., 2011, Friedman et al., 2011)

Raf - βTub60D

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - βTub97EF

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - blanks

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CCT1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Cdc37

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CG3651

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CG6961

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CG9775

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CG11417

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CG11999

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CG13117

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CkIIα

enzymatic study, autoradiography

(Stark et al., 2011)

Raf - cnk

two hybrid, anti tag coimmunoprecipitation, western blot, peptide massfingerprinting

(Maisonneuve et al., 2024, Friedman et al., 2011, Therrien et al., 1998)

Raf - CSN8

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - CtsL1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Dlc90F

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - drk

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Dsor1

anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot, two hybrid

(Maisonneuve et al., 2024, Friedman et al., 2011, Therrien et al., 1998)

Raf - eEF2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - eIF4A

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Eip63E

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - fmt

anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot

(Friedman et al., 2011, Friedman et al., 2011)

Raf - galla-2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - GckIII

anti tag coimmunoprecipitation, anti tag western blot

(Friedman and Perrimon, 2006)

Raf - GCS2β

anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot

(Friedman et al., 2011, Friedman et al., 2011)

Raf - Gfat2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Gyf

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Hrb87F

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Hsp60A

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Hsp70Ab

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Hsp83

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Ipo9

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Kcmf1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - krz

anti tag coimmunoprecipitation, anti tag western blot

(Tipping et al., 2010)

Raf - ksr

anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot

(Maisonneuve et al., 2024, Friedman et al., 2011)

Raf - Lk6

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Mcad

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - morgue

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - NAT1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - nesd

anti tag coimmunoprecipitation, anti tag western blot

(Friedman et al., 2011)

Raf - Nfs1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Nup50

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Past1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Pdha1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - PH4αEFB

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - pic

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - PpV

anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting

(Friedman et al., 2011, Friedman et al., 2011)

Raf - Psa

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Pyk

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Rack1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Rap1

anti tag coimmunoprecipitation, anti tag western blot, two hybrid

(Ding et al., 2010, Mishra et al., 2005)

Raf - Ras64B

pull down, autoradiography

(Vega-Cuesta et al., 2020, Yang and Terman, 2012)

Raf - Ras85D

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

(Yang and Terman, 2012, Ding et al., 2010, Mishra et al., 2005)

Raf - rl

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpL3

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpL17

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpL27

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpL27A

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpL28

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpL35A

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Rpn1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpS15Aa

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpS18

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpS26

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - RpS27A

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Rpt1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Rpt5

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - ScsβA

anti tag coimmunoprecipitation, anti tag western blot

(Friedman et al., 2011)

Raf - SERCA

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - sesB

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - shv

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - sip2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Slik

anti tag coimmunoprecipitation, anti tag western blot

(Hipfner and Cohen, 2003)

Raf - SPARC

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Ssb-c31a

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - TBPH

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Tim23

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - Tkt

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - wal

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Raf - yata

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (14 alleles)

Raf

Models Based on Experimental Evidence ( 5 )

Allele

Disease

Evidence

References

Raf^F22.hs

model of cancer

CEA

(Zhao et al., 2021)

Raf^UAS.F179

model of cancer

CEA with RhoGEF2^RE.UAS

(Khoo et al., 2013)

CEA

(Xu et al., 2023, Ren et al., 2022, Brás et al., 2021, Lee et al., 2021, Pfeifle et al., 2019)

CEA with scrib¹

(Yang et al., 2022)

model of carcinoma

CEA with scrib¹

(Wei et al., 2021, Uhlirova et al., 2005)

Raf^{A572E.UAS.Tag:FLAG}

model of cancer

CEA

(Pfeifle et al., 2019)

Raf^CA.UAS.cUa

model of high grade glioma

CEA

(Xie et al., 2023)

Raf^RNAi.UAS.cUa

model of cardiomyopathy

CEA

(Yu et al., 2013)

Modifiers Based on Experimental Evidence ( 10 )

Allele

Disease

Interaction

References

Raf¹²

ameliorates neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2006)

Raf⁷

ameliorates multiple endocrine neoplasia type 2B

modeled by Ret^MEN2B.UAS

(Sonoshita et al., 2018)

Raf^DN.UAS

ameliorates carcinoma

modeled by Ras85D^V12.UAS

(Zoranovic et al., 2018)

Raf^F22.hs

model of cancer

is ameliorated by Atg1^HMS02750

(Zhao et al., 2021)

is ameliorated by slif^UY681

(Zhao et al., 2021)

is exacerbated by Atg101^6h

(Zhao et al., 2021)

is ameliorated by Atg16^MI00187

(Zhao et al., 2021)

is ameliorated by Atg5^HMS01244

(Zhao et al., 2021)

is ameliorated by Atg6^HMS01483

(Zhao et al., 2021)

is ameliorated by Balat^HMC06377

(Zhao et al., 2021)

is ameliorated by CarT^HMC04919

(Zhao et al., 2021)

is ameliorated by Cat^UAS.cAa

(Zhao et al., 2021)

is ameliorated by bsk^HMS00777

(Zhao et al., 2021)

is ameliorated by bsk^K53R.UAS

(Zhao et al., 2021)

is ameliorated by slif^HMC05846

(Zhao et al., 2021)

Raf^UAS.F179

model of cancer

is ameliorated by Atg1^UAS.cSa

(Lee et al., 2021)

is ameliorated by dind^{RNAi.UAS.RNAi}

(Ren et al., 2022)

is exacerbated by Mps1^GL00184

(Brás et al., 2021)

is exacerbated by Mps1^HMS01546

(Brás et al., 2021)

is exacerbated by mad2^GLC01381

(Brás et al., 2021)

exacerbates gastrointestinal system cancer

modeled by Apc2^g10, Apc^Q8

(Wang et al., 2013)

exacerbates carcinoma

modeled by ft^k07918

(Garoia et al., 2005)

modeled by ft^G-rv

(Garoia et al., 2005)

model of carcinoma

is ameliorated by hep^Act.UAS

(Uhlirova et al., 2005)

exacerbates cancer

modeled by Mps1^GL00184

(Brás et al., 2021)

modeled by Mps1^HMS01546

(Brás et al., 2021)

modeled by mad2^GLC01381

(Brás et al., 2021)

exacerbates hematologic cancer

modeled by mxc¹

(Kurihara et al., 2020)

Raf^XS-2541

ameliorates carcinoma

modeled by Ras85D^V12.UAS

(Karim and Rubin, 1998)

modeled by Ras85D^V12.ey

(Karim and Rubin, 1998)

Raf^GD9831

ameliorates Huntington's disease

modeled by Hsap\HTT^NT.128Q.UAS

(Miller et al., 2012)

Raf^KK100982

ameliorates autosomal dominant cerebellar ataxia

modeled by Hsap\ATXN1^82Q.UAS

(Park et al., 2013)

Raf^GL01125

ameliorates hematologic cancer

modeled by mxc¹

(Kurihara et al., 2020)

Raf^CA.UAS.cUa

model of high grade glioma

is ameliorated by slo^JF02146

(Xie et al., 2023)

is ameliorated by slo^KO

(Xie et al., 2023)

is exacerbated by slo^UAS.cXa

(Xie et al., 2023)

is ameliorated by slo^HMC04093

(Xie et al., 2023)

Hsap\BRAF

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

Hsap\BRAF^V600E.UAS

model of melanoma

CEA

(Volkhardt et al., 2018)

Hsap\BRAF^W531C.UAS

model of Noonan syndrome

CEA

(Das et al., 2021)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

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\BRAF^V600E.UAS

P{UAS-hBRAF.V600E}

Hsap\BRAF^{V600E.UAS.Tag:FLAG}

P{UAS-hBRAF.V600E.FLAG}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

Raf^{A572E.UAS.Tag:FLAG}

P{UAS-Raf.A572E.FLAG}

w^*; P{UAS-Raf.gof}F179

Raf^F22.hs

P{Hsp70-Draf.gof}

w^*; P{Hsp70-Draf.gof}3/TM3, Sb¹

Raf^DN.UAS

P{UAS-raf^DN}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

w¹¹¹⁸; P{GD9831}v20909

y¹ v¹; P{TRiP.JF01185}attP2

Raf^JF01483

P{TRiP.JF01483}

y¹ v¹; P{TRiP.JF01483}attP2

y¹ v¹; P{TRiP.GL01125}attP40

Raf^HMC03854

P{TRiP.HMC03854}

y¹ sc^* v¹ sev²¹; P{TRiP.HMC03854}attP2

Raf^HMC04133

P{TRiP.HMC04133}

y¹ v¹; P{TRiP.HMC04133}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Raf⁹²⁶

loss of function allele

ethyl methanesulfonate

Raf^raf-1

amorphic allele - genetic evidence

nitrosomethyl urea

Raf^XS-2541

X ray

Raf^raf-2

loss of function allele

Raf¹

amorphic allele - genetic evidence

X ray

Raf^400B8

amorphic allele - genetic evidence

1,2-dichloroethane

Raf¹¹

amorphic allele - genetic evidence

spontaneous

Raf¹¹/FM6, l(1)FMa¹/Dp(1;Y)Bar^Sw⁺y⁺

Raf^C2Z2

amorphic allele - genetic evidence

ethyl methanesulfonate

Raf⁷

loss of function allele

ethyl methanesulfonate

Raf⁷/FM7a

Raf¹²

hycanthon methanesulfonate

y¹ w^a Raf¹²/FM6, wⁱ Myc⁺

Raf¹⁰⁷

amorphic allele - genetic evidence

ethyl methanesulfonate

Raf⁶

amorphic allele - genetic evidence

ethyl methanesulfonate

Raf^X1

amorphic allele - genetic evidence

X ray

Raf⁵

amorphic allele - genetic evidence

ethyl methanesulfonate

References (6)

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