The fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily

doi:10.1016/0092-8674(91)90359-7

Cell

Volume 67, Issue 5, 29 November 1991, Pages 853-868

https://doi.org/10.1016/0092-8674(91)90359-7 Get rights and content

Abstract

Recessive lethal mutations in the fat locus of Drosophila cause hyperplastic, tumor-like overgrowth of larval imaginal discs, defects in differentiation and morphogenesis, and death during the pupal stage. Clones of mutant cells induced by mitotic recombination demonstrate that the overgrowth phenotype is cell autonomous. Here we show that the fat locus encodes a novel member of the cadherin gene superfamily: an enormous transmembrane protein of over 5000 amino acids with a putative signal sequence, 34 tandem cadherin domains, four EGF-like repeats, a transmembrane domain, and a novel cytoplasmic domain. Two recessive lethal alleles contain alterations in the fat coding sequence, and the dominant fat allele, Gull, contains an insertion of a transposable element in the 33rd cadherin domain. Thus, this novel member of the cadherin gene superfamily functions as a tumor suppressor gene and is required for correct morphogenesis.

References (80)

S.F. Altschul et al.
Basic local alignment search tool
J. Mol. Biol.
(1990)
J. Austin et al.
Transcript analysis of glp-1 and lin-12, homologous genes required for cell interactions during development of C. elegans
Cell
(1989)
A.J. Bieber et al.
Drosophila neuroglian: a member of the immunoglobulin superfamily with extensive homology to the vertebrate neural adhesion molecule L1
Cell
(1989)
P.J. Bryant et al.
Intrinsic growth control in the imaginal primordia of Drosophila, and the autonomous action of a lethal mutation causing overgrowth
Dev. Biol.
(1985)
P.J. Bryant et al.
Giant and duplicated imaginal discs in a new lethal mutant of Drosophila melanogaster
Dev. Biol.
(1971)
P.J. Bryant et al.
Mutations at the fat locus interfere with cell proliferation control and epithelial morphogenesis in Drosophila
Dev. Biol.
(1988)
R.J. Detrick et al.
The effects of N-cadherin misexpression of morphogenesis in Xenopus embryos
Neuron
(1990)
T. Elkins et al.
Genetic analysis of a Drosophila neural cell adhesion molecule: interaction of fasciclin I and Abelson tyrosine kinase mutations
Cell
(1990)
L. Goodwin et al.
Desmoglein shows extensive homology to the cadherin family of cell adhesion molecules
Biochem. Biophys. Res. Commun.
(1990)
G. Grenningloh et al.
Genetic analysis of growth cone guidance in Drosophila: fasciclin II functions as a neuronal recognition molecule
Cell
(1991)

K. Hatta et al.

Spatial and temporal expression pattern of N-cadherin cell adhesion molecules correlated with morphogenetic processes of chicken embryos

Dev. Biol.

(1987)

V.A. Jursnich et al.

Defective gap-junctional communication associated with imaginal disc overgrowth and degeneration caused by mutations of the dco gene in Drosophila

Dev. Biol.

(1990)

C. Klämbt et al.

The Drosophila melanogaster I(2)gl gene encodes a protein homologous to the cadherin cell-adhesion molecule family

Dev. Biol.

(1989)

M. Leptin et al.

The function of PS integrins during Drosophila embryogenesis

Cell

(1989)

P. Martin et al.

Studies of l(3)c43^hs1—a polyphasic, temperature-sensitive mutant of Drosophila melanogaster with a variety of imaginal disc defects

Dev. Biol.

(1977)

D.J. Montell et al.

Drosophila substrate adhesion molecule: sequence of laminin B1 chain reveals domains of homology with mouse

Cell

(1988)

C. Murphy

Cell death and autonomous gene action in lethals affecting imaginal discs in Drosophila melanogaster

Dev. Biol.

(1974)

A. Nose et al.

Expressed recombinant cadherins mediate cell sorting in model systems

Cell

(1988)

A. Nose et al.

Localization of specificity determining sites in cadherin cell adhesion molecules

Cell

(1990)

M. Ozawa et al.

Single amino acid substitutions in one Ca²⁺ binding site of uvomorulin abolish the adhesive function

Cell

(1990)

B.M. Shepherd et al.

Structure of circular copies of the 412 transposable element present in Drosophila melanogaster tissue culture cells, and isolation of a free 412 long terminal repeat

J. Mol. Biol.

(1984)

P.M. Snow et al.

Fasciclin III: a novel homophilic adhesion molecule in Drosophila

Cell

(1989)

M. Stewart et al.

The recovery and preliminary characterization of X chromosome mutants affecting imaginal discs of Drosophila melanogaster

Dev. Biol.

(1972)

M. Takeichi

Cadherins: a molecular family essential for selective cell-cell adhesion and animal morphogenesis

Trends Genet.

(1987)

D. Van Vactor et al.

Analysis of mutants in chaoptin, a photoreceptor cell-specific glycoprotein in Drosophila, reveals its role in cellular morphogenesis

Cell

(1988)

K.A. Wharton et al.

Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats

Cell

(1985)

B.M. Will et al.

Nucleotide sequence of terminal repeats of 412 transposable elements of Drosophila melanogaster: a similarity to proviral long terminal repeats and its implications for the mechanism of transposition

J. Mol. Biol.

(1981)

D.F. Woods et al.

Molecular cloning of the lethal (1)discs large-1 oncogene of Drosophila

Dev. Biol.

(1989)

D.F. Woods et al.

The discs-large tumor suppressor gene of Drosophila encodes a guanylate kinase homolog localized at septate junctions

Cell

(1991)

J. Yochem et al.

glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins

Cell

(1989)

K. Zinn et al.

Sequence analysis and neuronal expression of fasciclin I in grasshopper and Drosophila

Cell

(1988)

M. Bevilacqua et al.

Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins

Science

(1989)

D.L. Brower et al.

Requirement for integrins during Drosophila wing development

Nature

(1989)

P.J. Bryant

Experimental and genetic analysis of growth and cell proliferation in Drosophila imaginal discs

J.A. Campos-Ortega et al.

The embryonic development of Drosophila melanogaster

(1985)

J.E. Collins et al.

Cloning and sequence analysis of desmosomal glycoproteins 2 and 3 (desmocollins): cadherin-like desmosomal adhesion molecules with heterogeneous cytoplasmic domains

J. Cell Biol.

(1991)

G.M. Edelman et al.

Cellular expression of liver and neural cell adhesion molecules after transfection with their cDNAs results in specific cell-cell binding

E.R. Fearon et al.

Identification of a chromosome 18q gene that is altered in colorectal cancers

Science

(1990)

D.J. Finnegan et al.

Repeated gene families in Drosophila melanogaster

T. Fujimori et al.

Ectopic expression of N-cadherin perturbs histogenesis in Xenopus embryos

Development

(1990)

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ArticleThe fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily

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Article
The fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily