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General Information
Name
cancer, epithelial, LLGL-YAP1-related
FlyBase ID
FBhh0000590
Disease Ontology Term
Parent Disease
OMIM
Overview

This model of epithelial cancer uses the Drosophila Scribble polarity complex gene l(2)gl in combination with a transcriptional co-activator regulated by the Hippo signaling pathway, the Drosophila gene yki. The highly conserved Scribble polarity complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. One of the human gene orthologous to Dmel\yki, YAP1, is known to play a role in the development and progression of multiple cancers. See also 'cancer, epithelial, Scribble-complex-related' (FBhh0000586) and 'cancer, epithelial, RAS-LLGL-related' (FBhh0000588).

In human, there are two genes orthologous to Dmel\l(2)gl, the cytoskeletal proteins LLGL1 and LLGL2. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for l(2)gl; an amorphic allele has been created via gene targeting and recombination. A tagged wild-type transgene of human Hsap\LLGL1 has been introduced into flies; partial heterologous rescue (functional complementation) of the homozygous Dmel\l(2)gl lethal phenotype is observed.

Animals homozygous for loss-of-function mutations of Dmel\l(2)gl typically die during the larval stage. Somatic clones that are homozygous for loss-of-function mutations of l(2)gl exhibit a cell polarity defect; mutant cells are eliminated from mosaic epithelia by cell competition. Multiple physical and many genetic interactions for Dmel\l(2)gl have been described; see below and in the gene report for l(2)gl.

In human, there are two genes orthologous to Dmel\yki, YAP1 and WWTR1. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for yki; an amorphic allele has been created via gene targeting and recombination. Multiple UAS constructs of the human Hsap\YAP1 gene have been introduced into flies, including wild-type and genes with mutations eliminating phosphorylation sites.

Animals homozygous for an amorphic mutation of Dmel\yki die as late embryos and early first instar larvae. Somatic clones are difficult to recover and are very small, indicating that complete loss of function is virtually cell-lethal. Models of cancer involving Dmel\yki use a constitutively active form or drive overexpression of a wild-type gene. MANY physical and genetic interactions for Dmel\yki have been described; see below and in the gene report for yki.

Clones of cells with an amorphic mutation of Dmel\l(2)gl and overexpression of Dmel\yki cause overgrowth of mutant cells in the wing pouch, eventually developing into tumors.

[updated Aug. 2017 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, LLGL-YAP1-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information

YAP1 encodes a transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway; it thus plays a key role development, growth, repair, and homeostasis. YAP1 is known to play a role in the development and progression of multiple cancers. [Gene Cards, YAP1; 2017.08.01]

LLGL1 and LLGL2 encode cortical cytoskeleton proteins found in a complex involved in maintaining cell polarity and epithelial integrity, the Scribble Cell Polarity Complex. This complex plays a role in the initial phase of the establishment of epithelial cell polarity; it is involved in the regulation of mitotic spindle orientation, proliferation, differentiation, and tissue organization of neuroepithelial cells. [Gene Cards, LLGL1, LLGL2; 2017.08.01]

External links
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second human gene is WWTR1.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second human gene is LLGL2.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second human gene is LLGL1.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    lethal (2) giant larvae (l(2)gl) encodes a tumor suppressor protein that regulates cell polarity and asymmetric cell division. It acts on the basolateral side of epithelial cells, antagonizing the activity of apical complex proteins encoded by baz, par-6 and aPKC. [Date last reviewed: 2019-09-26]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate- to high-scoring ortholog of human LLGL1 and LLGL2 (1 Drosophila to 2 human). Dmel\l(2)gl shares 34-36% identity and 51-54% 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
    Gene Snapshot
    yorkie (yki) encodes a transcriptional co-activator protein that is negatively regulated by Hippo signaling, which promotes its cytoplasmic localization. It functions together with DNA binding proteins, such as the product of sd, to activate transcription of a wide range of downstream targets, including genes that promote growth. [Date last reviewed: 2019-03-21]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate-scoring ortholog of human YAP1 and WWTR1 (1 Drosophila to 2 human). Dmel\yki shares 31% identity and 45% similarity with YAP1; it shares 25% identity and 34% similarity with WWTR1.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (83 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
    anti bait coimmunoprecipitation, western blot, pull down, peptide massfingerprinting, anti tag coimmunoprecipitation, autoradiography, experimental knowledge based, anti tag western blot
    proximity ligation assay, fluorescence microscopy, pull down, Identification by mass spectrometry, anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    RNA-RNA
    Interacting group
    Assay
    References
    fluorescence technology
    RNA-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, quantitative reverse transcription pcr
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, anti tag western blot, protein complementation assay, peptide massfingerprinting
    anti tag coimmunoprecipitation, western blot, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot, pull down, western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti bait coimmunoprecipitation, peptide massfingerprinting
    anti bait coimmunoprecipitation, peptide massfingerprinting, anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, western blot
    enzymatic study, western blot
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, tag visualisation
    coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, pull down, anti tag western blot, peptide massfingerprinting, Identification by mass spectrometry
    pull down, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    enzymatic study, autoradiography, anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, pull down, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, peptide massfingerprinting
    anti bait coimmunoprecipitation, peptide massfingerprinting
    anti bait coimmunoprecipitation, peptide massfingerprinting
    anti bait coimmunoprecipitation, peptide massfingerprinting
    anti bait coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot, tandem affinity purification, Identification by mass spectrometry, peptide massfingerprinting, pull down
    anti bait coimmunoprecipitation, western blot, peptide massfingerprinting, pull down, anti tag western blot, anti tag coimmunoprecipitation
    anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot
    anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based, anti tag western blot
    anti bait coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    pull down, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    enzymatic study, autoradiography
    anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, peptide massfingerprinting
    experimental knowledge based
    two hybrid, pull down, anti tag western blot, anti tag coimmunoprecipitation, surface plasmon resonance, predetermined participant, western blot, peptide massfingerprinting, autoradiography, anti bait coimmunoprecipitation, fluorescent resonance energy transfer
    anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, pull down, molecular sieving, molecular weight, two hybrid, Identification by mass spectrometry, isothermal titration calorimetry, predetermined participant, nuclear magnetic resonance, peptide massfingerprinting
    anti tag coimmunoprecipitation, anti tag western blot, pull down, anti bait coimmunoprecipitation, western blot, peptide massfingerprinting
    pull down, western blot
    anti tag coimmunoprecipitation, western blot, bimolecular fluorescence complementation, fluorescence microscopy, proximity ligation assay
    anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot, pull down, peptide massfingerprinting
    two hybrid, anti tag coimmunoprecipitation, anti tag western blot, pull down, peptide massfingerprinting, enzymatic study, western blot, autoradiography
    Alleles Reported to Model Human Disease (Disease Ontology) (21 alleles)
    Models Based on Experimental Evidence ( 5 )
    Modifiers Based on Experimental Evidence ( 3 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 6 )
    Modifiers Based on Experimental Evidence ( 10 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    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
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    loss of function allele
    CRISPR/Cas9
    loss of function allele
    loss of function allele
    natural population
    amorphic allele - genetic evidence
    spontaneous
    spontaneous
    amorphic allele - molecular evidence
    ends-out gene targeting
    References (7)