FB2019_06, released Dec 19, 2019

Human Disease Model Report: cancer, epithelial, SCRIB-related

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General Information
Name
cancer, epithelial, SCRIB-related
FlyBase ID
FBhh0000587
Disease Ontology Term
Parent Disease
OMIM
Overview

The Scribble polarity complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. The eponymous Drosophila scrib gene is a cell polarity regulator originally isolated as a tumor suppressor gene (in flies); there are two orthologous genes in human, SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\scrib.

Loss of apical-basal polarity is an early event in the development of epithelial cancers. See human diseases model reports 'cancer, epithelial, Scribble-complex-related' (FBhh0000586), 'cancer, epithelial, RAS-SCRIB-related' (FBhh0000585), and 'cancer, epithelial, NOTCH-SCRIB-related' (FBhh0000679).

A tagged wild-type transgene of human Hsap\SCRIB has been introduced into flies; partial heterologous rescue (functional complementation) of homozygous Dmel\scrib loss-of-function phenotypes is observed.

Animals homozygous for loss-of-function mutations of Dmel\scrib typically die during the larval stage; imaginal discs exhibit morphology defects, such as increase in size (due to increased cell numbers) and disruption of monolayered epithelial organization. Many physical and genetic interactions for Dmel\scrib have been described; see below and in the gene report for scrib.

To create a context that more accurately emulates the clonal development of tumors, somatic clones have been used. Somatic scrib(-) clones induced in developing eye imaginal discs in larvae are observed to have abnormal morphology and show increased proliferation; however, a mechanism to eliminate such clones appears to come into play, since very little scrib(-) tissue is eventually observed in the adult eye. Based on effects of mutations that modulate JNK signaling, it is postulated that the elimination of scrib(-) cells is mediated, at least in part, via the JNK signaling pathway.

This system has been used to characterize gene combinations leading to tumorigenesis (see Related Diseases section, below).

[updated Jul.2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, epithelial, SCRIB-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
SCRIB is a cytoplasmic multi-modular scaffold protein targeted to epithelial adherens junctions and neuronal presynaptic compartments. SCRIB and its orthologs in vertebrates and invertebrates participate in cell polarization (summary by Nola et al., 2008; pubmed:18716323). [from OMIM:607733; 2017.08.01]
(OMIM, 2013-)
The SCRIB gene encodes a scaffold protein involved in cell polarization processes; it is involved in tumor suppression pathways. [from Gene Cards, SCRIB; 2017.08.01]
(FlyBase Curators, 2013-)
External links
Disease synonyms
cancer, epithelial, scribble-related
carcinoma, SCRIB-related
Search term: hyperplastic phenotype(s)
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
SCRIB; scribble planar cell polarity protein
D. melanogaster ortholog (based on DIOPT)
Dmel\scrib
(DIOPT, 2013-)
Comments on ortholog(s)
Many to one: 2 human to 1 Drosophila; the second human gene is LRRC1.
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Dmel\scrib
    Gene Snapshot
    scribble (scrib) encodes a scaffolding protein that is part of the conserved machinery regulating apicobasal polarity. It acts with the products of dlg1 and l(2)gl to distinguish the basolateral domain of epithelial cells and neuroblasts, via reciprocally antagonistic interactions with the aPKC/par-6 complex that impacts vesicle trafficking. The product of scrib also organizes synaptic architecture and is implicated in learning and memory. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Cellular component (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)
      Ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      H. sapiens (Human)
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (15 groups)
      scrib
      protein-protein
      Interacting group
      Assay
      References
      scrib
      anti tag coimmunoprecipitation, anti tag western blot
      (Gui et al., 2016)
      scrib - bark
      proximity ligation assay, fluorescence microscopy
      (Sharifkhodaei et al., 2019)
      scrib - dlg1
      proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation
      (Nakajima et al., 2019, Sharifkhodaei et al., 2019, Rui et al., 2017, Mathew et al., 2002)
      scrib - Gli
      proximity ligation assay, fluorescence microscopy
      (Sharifkhodaei et al., 2019)
      scrib - gukh
      isothermal titration calorimetry, predetermined participant, anti bait coimmunoprecipitation, western blot, x-ray crystallography
      (Caria et al., 2018, Mathew et al., 2002)
      scrib - Mad
      anti tag coimmunoprecipitation, anti tag western blot
      (Gui et al., 2016)
      scrib - Nrx-1
      anti tag coimmunoprecipitation, western blot, pull down
      (Rui et al., 2017)
      scrib - Pak
      anti tag coimmunoprecipitation, western blot
      (Bahri et al., 2010)
      scrib - Pak3
      anti tag coimmunoprecipitation, western blot
      (Cervantes-Sandoval et al., 2016, Bahri et al., 2010)
      scrib - Rab5
      anti tag coimmunoprecipitation, anti tag western blot
      (Gui et al., 2016)
      scrib - Rac1
      anti tag coimmunoprecipitation, western blot
      (Cervantes-Sandoval et al., 2016)
      scrib - tkv
      anti tag coimmunoprecipitation, anti tag western blot
      (Gui et al., 2016)
      scrib - Traf4
      pull down, autoradiography
      (Mathew et al., 2011)
      scrib - tsr
      anti tag coimmunoprecipitation, western blot
      (Cervantes-Sandoval et al., 2016)
      scrib - Vang
      pull down, autoradiography, two hybrid
      (Courbard et al., 2009)
      Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
      Hsap\SCRIB
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      Hsap\SCRIBUAS.EGFP
      model of  cancer
      CEA with scribj7B3
      (Dow et al., 2003)
      Modifiers Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Interaction
      References
      scrib
      Models Based on Experimental Evidence ( 4 )
      Modifiers Based on Experimental Evidence ( 4 )
      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
      Hsap\SCRIBUAS.EGFP
      P{UAS-EGFP-hScrib}
      w*; P{UAS-EGFP-hScrib}T3
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      scribGD11666
      P{GD11666}
      w1118 P{GD11666}v27430
      scribGD11663
      P{GD11663}
      scribKK101128
      P{KK101128}
      P{KK101128}VIE-260B
      scribKK103936
      P{KK103936}
      P{KK103936}VIE-260B
      scribKK106065
      P{KK106065}
      P{KK106065}VIE-260B
      scribJF03229
      P{TRiP.JF03229}
      y1 v1; P{TRiP.JF03229}attP2
      scribHMS01490
      P{TRiP.HMS01490}
      y1 sc* v1 sev21; P{TRiP.HMS01490}attP2
      scribNIG.31082R
      P{NIG.31082R}
      scribNIG.5462R
      P{NIG.5462R}
      scribGL00638
      P{TRiP.GL00638}
      y1 sc* v1 sev21; P{TRiP.GL00638}attP40
      scribHMS01993
      P{TRiP.HMS01993}
      y1 sc* v1 sev21; P{TRiP.HMS01993}attP40/CyO
      scribVDRC.cUa
      P{VDRC.scrib.U}
      scribHMJ21977
      P{TRiP.HMJ21977}
      y1 v1; P{TRiP.HMJ21977}attP40
      scribdsRNA.UAS
      P{UAS-scrib.RNAi}
      w*; P{UAS-scrib.RNAi}7L
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      scribj7B3
      P-element activity
      yd2 w1118 P{ey-FLP.N}2 P{5xglBS-lacZ.38-1}TPN1; P{neoFRT}82B P{lacW}scribj7B3/TM6B, P{Car20y}TPN1, Tb1
      scribird15
      loss of function allele
      ethyl methanesulfonate
      scrib1
      loss of function allele
      ethyl methanesulfonate
      scrib673
      loss of function allele
      ethyl methanesulfonate
      Dp(1;Y)BS; scrib673 e1/TM3, Ser1
      References (43)