FAT1 (FAT tumor suppressor homolog 1 (Drosophila))

2011-02-01 Kunzang Chosdol , Bhawana Dikshit , Subrata Sinha Affiliation

Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, India

Identity

HGNC

FAT1

LOCATION

4q35.2

LOCUSID

2195

ALIAS

CDHF7,CDHR8,FAT,ME5,hFat1

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

FAT1 gene is located on the chromosome 4q35.2 (Accession: NC_000004.11). The total length of the gene is 136050 bases (187509746 bp to 187630981 bp from pter) of reverse strand. There are 27 exons.
An alternate assembly suggested to be starting from 187745931 bp to 187881981 bp from pter.

Transcription

The length of the transcript is 14773 bps made from 27 exons (Accession: NM_005245.3).

Pseudogene

FAT tumor suppressor homolog 1 (Drosophila) pseudogene 1 (FAT1P1).
Other name: dJ697P8.1; sequence accession ID: AL050403; location chromosome: 20p12.2.

Proteins

Note

Known protein coding gene.

Protein names
Recommended name: protocadherin Fat 1.
Alternative names: Cadherin-related tumor suppressor homolog, Protein fat homolog, Cadherin family member 7.

Description

4588 aa (Accession: NP_005236.2).

Expression

Expressed in epithelial, endothelial and smooth muscle cells.

Localisation

Cell membrane; single-pass type I membrane protein.

Function

Could function as a cell-adhesion molecule, cell signalling molecule, and have a role in cell migration.
Fat in Drosophila acts via SWH signalling pathway as tumour suppressor gene. Homolog of SWH pathway molecules are present in human, so there is a possibility of acting FAT1 as an upstream regulator of SWH pathway in human.
In human, FAT1 expression is highest at the embryonic stages and diminishes later in adult life. In human fetal tissues, high levels of FAT1 transcripts were found in kidney, lungs, and eye epithelia, and the expression was found to be down regulated in the corresponding adult tissues, indicating the role of FAT1 in organ development. FAT1 also has a role in cell migration (Moeller et al., 2004; Tanoue and Takeichi, 2004) and found to be up-regulated in migrating cells, also crucial for efficient wound healing (Braun et al., 2007).
In Drosophila, fat is an upstream regulator of the Salvador-Wart-Hippo (SWH) signaling pathway (Cho et al., 2006; Bennett and Harvey, 2006). The signalling molecules of SWH pathway are conserved in mammals (figure below) but the role of FAT1 as an apical regulator of SWH pathway in human has not yet been established.

Salvador-Warts-Hippo pathway. Mammalian hippo signaling pathway shows homology with Drosophila pathway proteins (depicted in similar color and shape).

In Drosophila fat (ft) interacts with core kinase cascade via Expanded (Ex). The core kinase cascade includes kinase Hippo (hpo), adaptor proteins mats and Salvador (Sav) and kinase Warts. The core kinase cascade inhibits phosphorylation of transcriptional co-activator Yorkie (Yki) causing its translocation to nucleus where it binds to transcriptional activator Scalloped (Sd) and modulates gene expression.

In mammals, whether FAT1 is involved in hippo pathway regulation is not clear. The effector molecule, phospho-YAP, is reported to interact with p73 in the nucleus and promotes cell death. There is no p73 homolog known to be reported in Drosophila. YAP is also found to interact with other transcription factors and modulate gene expression, thus, the outcome of hippo pathway is context dependent.

Homology

Paralogs for FAT1 gene: FAT2, FAT3, FAT4.

Organism	Gene	Locus	Description	Similarity to human FAT1
Dog (Canis familiaris)	FAT1	Chr. 16	FAT tumor suppressor homolog 1 (Drosophila)	86.95(n), 91.17(a)
Pig (Sus scrofa)	FAT1	Chr. 17	FAT tumor suppressor homolog 1 (Drosophila)	86(n), 90(a)
Cow (Bos Taurus)	FAT1	Chr. 27	FAT tumor suppressor homolog 1 (Drosophila)	84.18(n) 89.93(a)
Rat (Rattus norvegicus)	Fat1	Chr. 16q11	FAT tumor suppressor homolog 1 (Drosophila)	82.93(n) 88.16(a)
Mouse (Mus musculus)	Fat1	Chr. 8 (25.00 cM)	FAT tumor suppressor homolog 1 (Drosophila)	82.51(n) 88.14(a)
Chicken (Gallus gallus)	FAT	Chr. 4	FAT tumor suppressor homolog 1 (Drosophila)	76.35(n) 81.43(a)
Zebrafish (Danio rerio)	fat1	Chr. 1	FAT tumor suppressor homolog 1	64.68(n) 64.82(a)
Fruit fly (Drosophila melanogaster)	ft and fat2	Chr. 2L (ft) Chr. 3L (fat2)	fat and fat2	ft - 42.8(n) 42(a), fat2 - 47.99(n) 39.02(a)
Worm (Caenorhabditis elegans)	cdh-4	Chr. III	Cadherin family	44.19(n) 30.89(a)
African malaria mosquito (Anopheles gambiae)	AgaP_AGAP011526	Chr. 3L	AGAP011526-PA	48.06(n) 39.5(a)

Orthologs for FAT1 gene from other species.

Mutations

Note

No known mutations. Single nucleotide polymorphism (SNPs): gene: FAT1 (ENSG00000083857).

Implicated in

Entity name

Various cancers

Note

FAT1, a member of the cadherin gene family, is homologue of Drosophila tumour suppressor gene fat. In Drosophila, fat gene is important in controlling cell proliferation during development and any defect in the expression of fat would lead to tumor development (Bryant et al., 1988). Dunne et al. (1995) have identified the human homologue and studied the tissue distribution of FAT transcripts in adult and fetal tissues.
Loss of heterozygosity and altered expression of FAT1 has been found in human glial tumors (Chosdol et al., 2009). Homozygous deletion of FAT1 gene was detected in oral cancer (Nakaya et al., 2007). Kwaepila et al. (2006) found higher FAT1 expression in more malignant form of breast cancer tissues by immunohistochemistry (IHC). There are studies showing LOH and/or deletion of the chromosome 4q34-35 region (which harbors FAT gene) in many tumors including gliomas. LOH was found in grade IV gliomas using microsatellite markers (Hu et al., 2002), though the gene itself has not been implicated. Other tumors like small cell lung carcinoma (Cho et al., 2002), hepatocellular carcinoma (Zhang et al., 2005; Chang et al., 2002) and cervical carcinoma (Backsch et al., 2005) etc showed alterations/LOH in the chromosomal 4q34-q35 locus and significant association of 4q34-q35 region with increased risk of progression of these tumors was suggested. Since the FAT gene is located in this region it may have an important role to play in the development and progression of these tumors.

Entity name

Astrocytic tumour

Note

Loss of heterozygosity and altered expression of FAT1 in astrocytic tumors (Chosdol et al., 2009).

Entity name

Breast cancer

Note

Increased FAT1 expression contributes to loss of duct formation, and increased cell migration and invasion in breast cancer (Kwaepila et al., 2006).

Entity name

Oral cancer

Note

Homozygous deletion of FAT in the cell lines and in primary oral cancers was studied. Homozygous deletion hot spots were observed in exon 1 (9/20, 45%) and exon 4 (7/20, 35%). The methylation status of the FAT CpG island in squamous cell carcinomas correlated negatively with its expression. Mutations in FAT is suggested as an important factor in the development of oral cancer. Moreover, loss of gene expression was identified in other types of squamous cell carcinoma (Nakaya et al., 2007).

Entity name

Psychiatric disorders

Note

Bipolar disorder: a positional cloning strategy, combined with association analysis have provided evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder (Blair et al., 2006).

Entity name

Cell migration

Note

FAT1 is known to play role in cell migration. FAT1 knockdown decreases cell migration in vascular smooth muscle cells (Hou et al., 2006; Hou and Sibinga, 2009). FAT1 plays an integrative role in regulating cell migration by participating in Ena/VASP-dependent regulation of cytoskeletal dynamics (Moeller et al., 2004).

Bibliography

Pubmed ID	Last Year	Title	Authors
15838843	2005	A region on human chromosome 4 (q35.1-->qter) induces senescence in cell hybrids and is involved in cervical carcinogenesis.	Backsch C et al
17045801	2006	Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway.	Bennett FC et al
16402135	2006	Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele.	Blair IP et al
17500054	2007	Differentially spliced isoforms of FAT1 are asymmetrically distributed within migrating cells.	Braun GS et al
3417051	1988	Mutations at the fat locus interfere with cell proliferation control and epithelial morphogenesis in Drosophila.	Bryant PJ et al
12048165	2002	Assessment of chromosomal losses and gains in hepatocellular carcinoma.	Chang J et al
16980976	2006	Delineation of a Fat tumor suppressor pathway.	Cho E et al
11971207	2002	Identification of tumor suppressor loci on the long arm of chromosome 4 in primary small cell lung cancers.	Cho ES et al
19126244	2009	Frequent loss of heterozygosity and altered expression of the candidate tumor suppressor gene 'FAT' in human astrocytic tumors.	Chosdol K et al
10741417	2000	Cloning and expression throughout mouse development of mfat1, a homologue of the Drosophila tumour suppressor gene fat.	Cox B et al
15749076	2005	Cloning and expression of the large zebrafish protocadherin gene, Fat.	Down M et al
8586420	1995	Molecular cloning and tissue expression of FAT, the human homologue of the Drosophila fat gene that is located on chromosome 4q34-q35 and encodes a putative adhesion molecule.	Dunne J et al
16682528	2006	The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals.	Hou R et al
19131340	2009	Atrophin proteins interact with the Fat1 cadherin and regulate migration and orientation in vascular smooth muscle cells.	Hou R et al
12215292	2002	Chromosome 14q may harbor multiple tumor suppressor genes in primary glioblastoma multiforme.	Hu J et al
16865240	2006	Comparative integromics on FAT1, FAT2, FAT3 and FAT4.	Katoh Y et al
16581652	2006	Immunohistological localisation of human FAT1 (hFAT) protein in 326 breast cancers. Does this adhesion molecule have a role in pathogenesis?	Kwaepila N et al
15922730	2005	Processing of the human protocadherin Fat1 and translocation of its cytoplasmic domain to the nucleus.	Magg T et al
15343270	2004	Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization.	Moeller MJ et al
17325662	2007	Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array.	Nakaya K et al
10072790	1999	Expression of the rat homologue of the Drosophila fat tumour suppressor gene.	Ponassi M et al
16979624	2006	The intracellular domain of the human protocadherin hFat1 interacts with Homer signalling scaffolding proteins.	Schreiner D et al
15148305	2004	Mammalian Fat1 cadherin regulates actin dynamics and cell-cell contact.	Tanoue T et al
15918185	2005	Clinicopathological significance of loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in China.	Zhang SH et al

Other Information

Locus ID:

NCBI: 2195
MIM: 600976
HGNC: 3595
Ensembl: ENSG00000083857

Variants:

dbSNP: 2195
ClinVar: 2195
TCGA: ENSG00000083857
COSMIC: FAT1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000083857	ENST00000441802	Q14517
ENSG00000083857	ENST00000507105	H0Y9C8
ENSG00000083857	ENST00000509537	D6RHE6
ENSG00000083857	ENST00000509647	D6RCE4
ENSG00000083857	ENST00000509927	H0Y8F5
ENSG00000083857	ENST00000512772	H0Y9H4
ENSG00000083857	ENST00000614102	A0A087WVP1

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
28366557	2017	FAT1 prevents epithelial mesenchymal transition (EMT) via MAPK/ERK signaling pathway in esophageal squamous cell cancer.	31
26905694	2016	FAT1 mutations cause a glomerulotubular nephropathy.	30
24550227	2014	Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness.	28
21617878	2011	Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin.	26
22116550	2012	The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis-relapse samples of precursor B-cell acute lymphoblastic leukemia.	26
17325662	2007	Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array.	25
30514309	2018	CircFAT1 sponges miR-375 to promote the expression of Yes-associated protein 1 in osteosarcoma cells.	23
21680732	2011	Dual processing of FAT1 cadherin protein by human melanoma cells generates distinct protein products.	18
29985391	2018	Assembly and activation of the Hippo signalome by FAT1 tumor suppressor.	18
22986533	2013	FAT1 acts as an upstream regulator of oncogenic and inflammatory pathways, via PDCD4, in glioma cells.	17

Citation

Kunzang Chosdol ; Bhawana Dikshit ; Subrata Sinha

FAT1 (FAT tumor suppressor homolog 1 (Drosophila))

Atlas Genet Cytogenet Oncol Haematol. 2011-02-01

Online version: http://atlasgeneticsoncology.org/gene/40533/fat1