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

Mahoney, Paul A.; Weber, Ursula; Onofrechuk, Patricia Leigh.; Biessmann, Harald; Bryant, Peter J.; Goodman, Corey S.

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

Cited by 441 publications

(299 citation statements)

References 61 publications

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“…1C) are thought to be the key to answering these questions. Ft is a large atypical cadherin molecule (>5,000 amino acids) as a transmembrane receptor with 34 cadherin domains in its extracellular region (Mahoney et al, 1991). In Drosophila, null alleles of ft are lethal, and mutants have overgrown imaginal discs.…”

Section: Introductionmentioning

confidence: 99%

Regulation of leg size and shape: Involvement of the Dachsous‐fat signaling pathway

Bando

Mito

Nakamura

et al. 2011

Developmental Dynamics

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How limb size and shape is regulated is a long-standing question in developmental and regeneration biology. Recently, the protocadherin Dachsous-Fat (Ds-Ft) signaling pathway has been found to be essential for wing development of the fly and leg regeneration of the cricket. The Ds-Ft signaling pathway is linked to the Warts-Hippo (Wts-Hpo) signaling pathway, leading to cell proliferation. Several lines of evidence have suggested that the Wts-Hpo signaling pathway is involved in the control of organ size, and that this pathway is regulated by Ds-Ft and Merlin-Expanded, which are linked to morphogens such as decapentaplegic/bone morphogenic protein, Wingless/Wnt, and epidermal growth factor. Here we review recent progress in elucidating mechanisms controlling leg size and shape in insects and vertebrates, focusing on the Ds-Ft signaling pathway. We also introduce a working model, Ds-Ft steepness model, to explain how steepness of the Ds-Ft gradient controls leg size along the proximodistal axis. Developmental Dynamics 240:1028-1041,

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Section: Introductionmentioning

confidence: 99%

Regulation of leg size and shape: Involvement of the Dachsous‐fat signaling pathway

Bando

Mito

Nakamura

et al. 2011

Developmental Dynamics

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“…Recessive lethal mutations in the fat locus in Drosophila caused hyperplastic, tumor-like overgrowth of imaginal discs, and defects in differentiation and morphogenesis (Mahoney et al, 1991). Although its mouse homolog (mfat) behaves differently not like a TSG since it is frequently expressed in highly proliferative cells, its human FAT was recently found to be frequently hypermethylated in tumors although no functional study was performed (Paz et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

Ying

Seng³

et al. 2005

Oncogene

245

288

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Protocadherins constitute the largest subgroup in the cadherin superfamily of cell adhesion molecules. Their major functions are poorly understood, although some are implicated in nervous system development. As tumorspecific promoter methylation is a marker for tumor suppressor genes (TSG), we searched for epigenetically inactivated TSGs using methylation-subtraction combined with pharmacologic demethylation, and identified the PCDH10 CpG island as a methylated sequence in nasopharyngeal carcinoma (NPC). PCDH10 is broadly expressed in all normal adult and fetal tissues including the epithelia, though at different levels. It resides at 4q28.3 -a region with hemizygous deletion detected by array-CGH in NPC cell lines; however, PCDH10 itself is not located within the deletion. In contrast, its transcriptional silencing and promoter methylation were frequently detected in multiple carcinoma cell lines in a biallelic way, including 12/12 nasopharyngeal, 13/16 esophageal, 3/4 breast, 5/5 colorectal, 3/4 cervical, 2/5 lung and 2/8 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell line. Aberrant methylation was further frequently detected in multiple primary carcinomas (82% in NPC, 42-51% for other carcinomas), but not normal tissues. The transcriptional silencing of PCDH10 could be reversed by pharmacologic demethylation with 5-aza-2 0 -deoxycytidine or genetic demethylation with double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Ectopic expression of PCDH10 strongly suppressed tumor cell growth, migration, invasion and colony formation. Although the epigenetic and genetic disruptions of several classical cadherins as TSGs have been well documented in tumors, this is the first report that a widely expressed protocadherin can also function as a TSG that is frequently inactivated epigenetically in multiple carcinomas.

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“…One such subgroup comprises the large Fat cadherins that exhibit an unusually large size from 4000 to 5000 amino acids, mainly due the large amount of cadherin repeats. The first molecule of this subgroup was identified in Drosophila as the gene product of the fat (ft) locus (3). Subsequently, proteins of the Fat subgroup were also discovered in mammals, and so far the following three have been characterized: human and mouse Fat1, respectively (4 -6), human Fat2 (7,8), and rat Fat3 (9).…”

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confidence: 99%

The fat-like Gene of Drosophila Is the True Orthologue of Vertebrate Fat Cadherins and Is Involved in the Formation of Tubular Organs

Castillejo-López¹,

Arias²,

Baumgärtner³

2004

Journal of Biological Chemistry

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Fat cadherins constitute a subclass of the large cadherin family characterized by the presence of 34 cadherin motifs. To date, three mammalian Fat cadherins have been described; however, only limited information is known about the function of these molecules. In this paper, we describe the second fat cadherin in Drosophila, fat-like (ftl). We show that ftl is the true orthologue of vertebrate fat-like genes, whereas the previously characterized tumor suppressor cadherin, fat, is more distantly related as compared with ftl. Ftl is a large molecule of 4705 amino acids. It is expressed apically in luminal tissues such as trachea, salivary glands, proventriculus, and hindgut. Silencing of ftl results in the collapse of tracheal epithelia giving rise to breaks, deletions, and sac-like structures. Other tubular organs such as proventriculus, salivary glands, and hindgut are also malformed or missing. These data suggest that Ftl is required for morphogenesis and maintenance of tubular structures of ectodermal origin and underline its similarity in function to a reported lethal mouse knock-out of fat1 where glomerular epithelial processes collapse. Based on our results, we propose a model where Ftl acts as a spacer to keep tubular epithelia apart rather than the previously described adhesive properties of the cadherin superfamily.

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

Cited by 441 publications

References 61 publications

Regulation of leg size and shape: Involvement of the Dachsous‐fat signaling pathway

Regulation of leg size and shape: Involvement of the Dachsous‐fat signaling pathway

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

The fat-like Gene of Drosophila Is the True Orthologue of Vertebrate Fat Cadherins and Is Involved in the Formation of Tubular Organs

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