Human Disease Model Report: cancer, multiple, NEK2-RET-related

General Information

Name

cancer, multiple, NEK2-RET-related

FlyBase ID

FBhh0001098

Disease Ontology Term

cancer

Parent Disease

OMIM

Overview

This report describes a Drosophila model of cancer that combines overexpression of the Dmel\Nek2 gene (orthologous to human NEK2) with a tumorigenic allele of Dmel\Ret (orthologous to human RET). NEK2 encodes a protein kinase involved in the control of centrosome separation and bipolar spindle formation. Overexpression of human NEK2 is observed in multiple different cancers and is thought to contribute to dysregulation of the centrosome cycle and aneuploidy. Addressed in this model is the possibility that the initial impact of NEK2 overexpression occurs at an earlier stage, and is not confined to increasing chromosomal instability.

The human NEK2 gene has not been introduced into flies.

A previously developed Drosophila model of thyroid cancer uses a mutation analogous to a human variant of RET implicated in multiple endocrine neoplasia (MEN2B; see FBhh0000014). Assessed in discs using a restricted expression pattern or somatic clones, Dmel\Ret mutant clones are observed to overproliferate, but cells are rarely observed to migrate into adjacent regions or tissues. Addition of Dmel\Nek2 overexpression results in a large number of migrated cells, including to distant parts of the body; patches of undifferentiated tissue and alteration of cytoskeletal organization are also observed. The metastatic phenotype is suppressed by reducing the activity of the PI3K/AKT pathway, either genetically or by the feeding of drugs that inhibit the pathway.

[updated Jul. 2019 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: cancer, multiple, NEK2-RET-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

NEK2 encodes a protein kinase involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. The protein is localized to the centrosome, and undetectable during G1 phase, but accumulates progressively throughout the S phase, reaching maximal levels in late G2 phase. [Gene Cards, NEK2; 2019.07.23]

(FlyBase Curators, 2013-)

External links

COSMIC gene: NEK2
COSMIC gene: RET
Gene2Function (human gene): NEK2
Gene Cards: NEK2
MedlinePlus (gene): NEK2
KEGG Disease Pathways: Pathways in Cancer
MARRVEL (human gene): NEK2
NCBI (Entrez) gene: NEK2; NIMA related kinase 2

Disease synonyms

Related Diseases

Related human health report(s)

cancer, multiple, NEK2-RAS-CSK(SRC)-related

multiple endocrine neoplasia, type IIB

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

NEK2; NIMA related kinase 2

D. melanogaster ortholog (based on DIOPT)

Dmel\Nek2

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: 1 human to 1 Drosophila; additional more distantly related gene(s) in both species.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\Nek2

Gene Snapshot

Nek2 (Nek2) encodes a Ser/Thr kinase belonging to the NIMA family of kinases. It regulates centrosome disjunction, bipolar spindle formation, and kinetochore microtubule dynamics during mitosis. It also participates in meiosis by regulating chromatin condensation events. [Date last reviewed: 2018-10-11]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Moderate- to high-scoring ortholog of human NEK2 (1 Drosophila to 1 human); additional more distantly related gene(s) in both species. Dmel\Nek2 shares 36% identity and 52% similarity with the human gene.

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\Ret

Gene Snapshot

Ret oncogene (Ret) encodes a cell surface receptor mediating dendrite development of class IV dendritic arborization sensory neurons. It interacts with integrins and mediates rac1 signaling to promote dendrite adhesion to the extracellular matrix. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Moderate-scoring ortholog of human RET (1 Drosophila to 1 human); additional more distantly related gene(s) in both species. Dmel\Ret shares 30% identity and 43% similarity with human RET.

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 (16 groups)

Nek2

protein-protein

Interacting group

Assay

References

Nek2

two hybrid

(Galletta et al., 2016)

Nek2 - ana1

two hybrid

(Galletta et al., 2016)

Nek2 - ana2

two hybrid

(Galletta et al., 2016)

Nek2 - asl

two hybrid

(Galletta et al., 2016)

Nek2 - aurA

two hybrid

(Galletta et al., 2016)

Nek2 - Cep135

two hybrid

(Galletta et al., 2016)

Nek2 - cnn

two hybrid

(Galletta et al., 2016)

Nek2 - Cp110

two hybrid

(Galletta et al., 2016)

Nek2 - dsh

enzymatic study, autoradiography, anti tag coimmunoprecipitation, western blot, peptide massfingerprinting

(Schertel et al., 2013)

Nek2 - Lk6

two hybrid

(Galletta et al., 2016)

Nek2 - Plp

two hybrid

(Galletta et al., 2016)

Nek2 - Sas-4

two hybrid

(Galletta et al., 2016)

Nek2 - spd-2

two hybrid

(Galletta et al., 2016)

Nek2 - tacc

two hybrid

(Galletta et al., 2016)

Ret

protein-protein

Interacting group

Assay

References

Ret - Gfrl

pull down, molecular weight estimation by staining, western blot, anti bait coimmunoprecipitation, anti tag western blot

(Myers et al., 2018, Saarenpää et al., 2017)

Ret - mys

anti tag coimmunoprecipitation, anti tag western blot

(Soba et al., 2015)

Alleles Reported to Model Human Disease (Disease Ontology) (13 alleles)

Nek2

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

Nek2^UAS.GFP

model of cancer

CEA

(Das et al., 2013)

CEA with Ret^MEN2B.UAS

(Das et al., 2013)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Nek2^UAS.GFP

exacerbates cancer

modeled by Csk^unspecified

(Das et al., 2013)

modeled by Ras85D^V12.UAS

(Das et al., 2013)

Ret

Models Based on Experimental Evidence ( 8 )

Allele

Disease

Evidence

References

Ret^GMR.PR

model of familial medullary thyroid carcinoma

CEA

(Vidal et al., 2005)

Ret^MEN2A.GMR

model of multiple endocrine neoplasia type 2A

CEA

(Read et al., 2005)

model of familial medullary thyroid carcinoma

CEA

(Vidal et al., 2005)

Ret^MEN2B.GMR

model of multiple endocrine neoplasia type 2B

CEA

(Read et al., 2005)

model of familial medullary thyroid carcinoma

CEA

(Vidal et al., 2005)

Ret^KK107206

model of Hirschsprung's disease

CEA

(Myers et al., 2018)

Ret^LM1

model of Hirschsprung's disease

CEA

(Myers et al., 2018)

Ret^LM2

model of Hirschsprung's disease

CEA

(Myers et al., 2018)

Ret^LM3

model of Hirschsprung's disease

CEA

(Myers et al., 2018)

Ret^MEN2B.UAS

model of cancer

CEA

(Das et al., 2013, Dar et al., 2012)

CEA with Nek2^UAS.GFP

(Das et al., 2013)

model of multiple endocrine neoplasia type 2B

CEA

(Fereres et al., 2019, Sonoshita et al., 2018)

Modifiers Based on Experimental Evidence ( 7 )

Allele

Disease

Interaction

References

Ret^MEN2A.GMR

model of multiple endocrine neoplasia type 2A

is exacerbated by Mi-2^S005504

(Read et al., 2005)

is ameliorated by kis^k10237

(Read et al., 2005)

is ameliorated by S^k09538a

(Read et al., 2005)

is exacerbated by Sin3A^ex4

(Read et al., 2005)

is exacerbated by msn^j1E2

(Read et al., 2005)

is ameliorated by S^IIN

(Read et al., 2005)

is exacerbated by Mi-2^S147412

(Read et al., 2005)

is ameliorated by spi¹

(Read et al., 2005)

is exacerbated by Sin3A⁰⁸²⁶⁹

(Read et al., 2005)

is ameliorated by Ras85D⁰⁶⁶⁷⁷

(Read et al., 2005)

is ameliorated by Delta^S049520

(Read et al., 2005)

is exacerbated by hh^rJ413

(Read et al., 2005)

is ameliorated by Delta^9P

(Read et al., 2005)

is ameliorated by ebi^k16213

(Read et al., 2005)

is ameliorated by spi^s3547

(Read et al., 2005)

is ameliorated by drk¹⁰⁶²⁶

(Read et al., 2005)

is exacerbated by hh²

(Read et al., 2005)

is ameliorated by Fak^UAS.Tag:HA

(Macagno et al., 2014)

Ret^MEN2B.GMR

model of multiple endocrine neoplasia type 2B

is exacerbated by Sin3A^HW52

(Read et al., 2005)

is ameliorated by drk^k02401

(Read et al., 2005)

is ameliorated by drk^k13809

(Read et al., 2005)

is ameliorated by kis^k13416

(Read et al., 2005)

is exacerbated by hh^rJ413

(Read et al., 2005)

is ameliorated by Delta^S049520

(Read et al., 2005)

is ameliorated by S^IIN

(Read et al., 2005)

is exacerbated by Sin3A⁰⁸²⁶⁹

(Read et al., 2005)

is ameliorated by spi⁰¹⁰⁶⁸

(Read et al., 2005)

is ameliorated by S^k09538a

(Read et al., 2005)

is exacerbated by msn⁰³³⁴⁹

(Read et al., 2005)

is exacerbated by Sin3A^k07401

(Read et al., 2005)

is exacerbated by Sin3A^k08919

(Read et al., 2005)

is ameliorated by S^k09530

(Read et al., 2005)

is exacerbated by hh²

(Read et al., 2005)

is ameliorated by hh^neo56

(Read et al., 2005)

is ameliorated by Delta^9P

(Read et al., 2005)

is exacerbated by Mi-2^S147412

(Read et al., 2005)

is ameliorated by ebi^k16213

(Read et al., 2005)

is exacerbated by Mi-2^j3D4

(Read et al., 2005)

is exacerbated by Mi-2^S047526

(Read et al., 2005)

is ameliorated by kis^k16510

(Read et al., 2005)

is ameliorated by drk¹⁰⁶²⁶

(Read et al., 2005)

is ameliorated by spi^s3547

(Read et al., 2005)

is exacerbated by Csk^j1D8

(Read et al., 2005)

is exacerbated by hh^AC

(Read et al., 2005)

is ameliorated by kis^k10237

(Read et al., 2005)

is ameliorated by spi¹

(Read et al., 2005)

is ameliorated by Ras85D⁰⁶⁶⁷⁷

(Read et al., 2005)

is exacerbated by msn^j1E2

(Read et al., 2005)

is exacerbated by Sin3A^ex4

(Read et al., 2005)

is ameliorated by Ras85D^ΔC40B

(Read et al., 2005)

is exacerbated by Mi-2^S005504

(Read et al., 2005)

model of cancer

is exacerbated by Sin3A^KK100700

(Das et al., 2013)

Ret^K805A.UAS

DOES NOT ameliorate neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

Ret^HMC03102

ameliorates lung adenocarcinoma

modeled by Hsap\KIF5B::Hsap\RET^UAS.cDa

(Das and Cagan, 2017)

Ret^MEN2A.UAS

model of multiple endocrine neoplasia type 2A

is exacerbated by Fak^CG1

(Macagno et al., 2014)

is ameliorated by Fak^UAS.Tag:HA

(Macagno et al., 2014)

is exacerbated by Fak^5-SZ-3124

(Macagno et al., 2014)

Ret^MEN2B.UAS

DOES NOT ameliorate Parkinson's disease

modeled by Pink1^B9

(Klein et al., 2014)

ameliorates Parkinson's disease

modeled by Pink1^B9

(Klein et al., 2014)

model of multiple endocrine neoplasia type 2B

is exacerbated by Lk6²

(Sonoshita et al., 2018)

is ameliorated by Lk6^RNAi.UAS.cUa

(Sonoshita et al., 2018)

is ameliorated by Raf⁷

(Sonoshita et al., 2018)

is ameliorated by Irk2^DN.UAS

(Fereres et al., 2019)

is ameliorated by SCAR^GD11380

(Fereres et al., 2019)

is ameliorated by dia^GL00408

(Fereres et al., 2019)

Ret^{UAS.Tag:LOV(VfAU1)}

ameliorates Parkinson's disease 6

modeled by Pink1^B9

(Ingles-Prieto 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

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

Ret^{UAS.Tag:LOV(VfAU1)}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Nek2^GD9324

P{GD9324}

w¹¹¹⁸; P{GD9324}v40052

y¹ v¹; P{TRiP.HM05088}attP2/TM3, Sb¹

Nek2^GL00235

P{TRiP.GL00235}

y¹ sc^* v¹ sev²¹; P{TRiP.GL00235}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.HMS04457}attP40

Nek2^HMC05100

P{TRiP.HMC05100}

y¹ sc^* v¹ sev²¹; P{TRiP.HMC05100}attP2

w¹¹¹⁸; P{GD45}v843

y¹ v¹; P{TRiP.JF01968}attP2

y¹ v¹; P{TRiP.HMC03102}attP40

Ret^HMC04143

P{TRiP.HMC04143}

y¹ v¹; P{TRiP.HMC04143}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Ret^KO

amorphic allele - molecular evidence

ends-out gene targeting

Ret^LM1

amorphic allele - molecular evidence

CRISPR/Cas9

w^*/Dp(1;Y)y⁺, P{ActGFP}SH1; Ret^LM1

Ret^LM2

amorphic allele - molecular evidence

CRISPR/Cas9

Ret^LM3

amorphic allele - molecular evidence

CRISPR/Cas9

w^*; Ret^LM3/CyO, P{ActGFP}JMR1

References (4)

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