| Written | 2011-02 | Kunzang Chosdol, Bhawana Dikshit, Subrata Sinha |
| Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, India |
| Identity |
| Alias_names | FAT |
| FAT tumor suppressor (Drosophila) homolog | |
| FAT tumor suppressor homolog 1 (Drosophila) | |
| Alias_symbol (synonym) | CDHF7 |
| CDHR8 | |
| Other alias | ME5 |
| hFat1 | |
| HGNC (Hugo) | FAT1 |
| LocusID (NCBI) | 2195 |
| Atlas_Id | 40533 |
| Location | 4q35.2 [Link to chromosome band 4q35] |
| Location_base_pair | Starts at 186587783 and ends at 186723833 bp from pter ( according to hg19-Feb_2009) [Mapping FAT1.png] |
| Fusion genes (updated 2016) | FAT1 (4q35.2) / ACSL1 (4q35.1) | FAT1 (4q35.2) / CFAP97 (4q35.1) | FAT1 (4q35.2) / FAT1 (4q35.2) |
| FAT1 (4q35.2) / SPARC (5q33.1) | FBRSL1 (12q24.33) / FAT1 (4q35.2) | STMN2 (8q21.13) / FAT1 (4q35.2) | |
| Note | FAT1 is an ortholog of the Drosophila tumor suppressor gene 'fat'. In Drosophila, it is essential for controlling cell proliferation during development. The gene product is a member of the cadherin superfamily, characterized by the presence of cadherin-type repeats. In addition to containing 34 tandem cadherin-type repeats, the gene product has five epidermal growth factor (EGF)-like repeats and one laminin A-G domain. This gene is expressed at high levels in a number of fetal epithelia. Its product probably functions as an adhesion molecule and/or signaling receptor, and is likely to be important in developmental processes and cell-cell communication. |
| 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. |
| Protein |
| Note | Known protein coding gene. Protein names | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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.
|
| Mutations |
| Note | No known mutations. Single nucleotide polymorphism (SNPs): gene: FAT1 (ENSG00000083857). |
| Implicated in |
| Note | |
| Entity | 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 | Astrocytic tumour |
| Note | Loss of heterozygosity and altered expression of FAT1 in astrocytic tumors (Chosdol et al., 2009). |
| Entity | 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 | 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 | 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 | 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 |
| A region on human chromosome 4 (q35.1-->qter) induces senescence in cell hybrids and is involved in cervical carcinogenesis. |
| Backsch C, Rudolph B, Kuhne-Heid R, Kalscheuer V, Bartsch O, Jansen L, Beer K, Meyer B, Schneider A, Dust M. |
| Genes Chromosomes Cancer. 2005 Jul;43(3):260-72. |
| PMID 15838843 |
| Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. |
| Bennett FC, Harvey KF. |
| Curr Biol. 2006 Nov 7;16(21):2101-10. Epub 2006 Oct 12. |
| PMID 17045801 |
| Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele. |
| Blair IP, Chetcuti AF, Badenhop RF, Scimone A, Moses MJ, Adams LJ, Craddock N, Green E, Kirov G, Owen MJ, Kwok JB, Donald JA, Mitchell PB, Schofield PR. |
| Mol Psychiatry. 2006 Apr;11(4):372-83. |
| PMID 16402135 |
| Differentially spliced isoforms of FAT1 are asymmetrically distributed within migrating cells. |
| Braun GS, Kretzler M, Heider T, Floege J, Holzman LB, Kriz W, Moeller MJ. |
| J Biol Chem. 2007 Aug 3;282(31):22823-33. Epub 2007 May 11. |
| PMID 17500054 |
| Mutations at the fat locus interfere with cell proliferation control and epithelial morphogenesis in Drosophila. |
| Bryant PJ, Huettner B, Held LI Jr, Ryerse J, Szidonya J. |
| Dev Biol. 1988 Oct;129(2):541-54. |
| PMID 3417051 |
| Assessment of chromosomal losses and gains in hepatocellular carcinoma. |
| Chang J, Kim NG, Piao Z, Park C, Park KS, Paik YK, Lee WJ, Kim BR, Kim H. |
| Cancer Lett. 2002 Aug 28;182(2):193-202. |
| PMID 12048165 |
| Delineation of a Fat tumor suppressor pathway. |
| Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine KD. |
| Nat Genet. 2006 Oct;38(10):1142-50. Epub 2006 Sep 17. |
| PMID 16980976 |
| Identification of tumor suppressor loci on the long arm of chromosome 4 in primary small cell lung cancers. |
| Cho ES, Chang J, Chung KY, Shin DH, Kim YS, Kim SK, Kim SK. |
| Yonsei Med J. 2002 Apr;43(2):145-51. |
| PMID 11971207 |
| Frequent loss of heterozygosity and altered expression of the candidate tumor suppressor gene 'FAT' in human astrocytic tumors. |
| Chosdol K, Misra A, Puri S, Srivastava T, Chattopadhyay P, Sarkar C, Mahapatra AK, Sinha S. |
| BMC Cancer. 2009 Jan 7;9:5. |
| PMID 19126244 |
| Cloning and expression throughout mouse development of mfat1, a homologue of the Drosophila tumour suppressor gene fat. |
| Cox B, Hadjantonakis AK, Collins JE, Magee AI. |
| Dev Dyn. 2000 Mar;217(3):233-40. |
| PMID 10741417 |
| Cloning and expression of the large zebrafish protocadherin gene, Fat. |
| Down M, Power M, Smith SI, Ralston K, Spanevello M, Burns GF, Boyd AW. |
| Gene Expr Patterns. 2005 Apr;5(4):483-90. |
| PMID 15749076 |
| 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, Hanby AM, Poulsom R, Jones TA, Sheer D, Chin WG, Da SM, Zhao Q, Beverley PC, Owen MJ. |
| Genomics. 1995 Nov 20;30(2):207-23. |
| PMID 8586420 |
| The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals. |
| Hou R, Liu L, Anees S, Hiroyasu S, Sibinga NE |
| J Cell Biol. 2006 May 8;173(3):417-29. |
| PMID 16682528 |
| Atrophin proteins interact with the Fat1 cadherin and regulate migration and orientation in vascular smooth muscle cells. |
| Hou R, Sibinga NE. |
| J Biol Chem. 2009 Mar 13;284(11):6955-65. Epub 2009 Jan 7. |
| PMID 19131340 |
| Chromosome 14q may harbor multiple tumor suppressor genes in primary glioblastoma multiforme. |
| Hu J, Jiang C, Ng HK, Pang JC, Tong CY. |
| Chin Med J (Engl). 2002 Aug;115(8):1201-4. |
| PMID 12215292 |
| Comparative integromics on FAT1, FAT2, FAT3 and FAT4. |
| Katoh Y, Katoh M. |
| Int J Mol Med. 2006 Sep;18(3):523-8. |
| PMID 16865240 |
| Immunohistological localisation of human FAT1 (hFAT) protein in 326 breast cancers. Does this adhesion molecule have a role in pathogenesis? |
| Kwaepila N, Burns G, Leong AS. |
| Pathology. 2006 Apr;38(2):125-31. |
| PMID 16581652 |
| Processing of the human protocadherin Fat1 and translocation of its cytoplasmic domain to the nucleus. |
| Magg T, Schreiner D, Solis GP, Bade EG, Hofer HW. |
| Exp Cell Res. 2005 Jul 1;307(1):100-8. Epub 2005 Apr 15. |
| PMID 15922730 |
| Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization. |
| Moeller MJ, Soofi A, Braun GS, Li X, Watzl C, Kriz W, Holzman LB. |
| EMBO J. 2004 Oct 1;23(19):3769-79. Epub 2004 Sep 2. |
| PMID 15343270 |
| Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array. |
| Nakaya K, Yamagata HD, Arita N, Nakashiro KI, Nose M, Miki T, Hamakawa H. |
| Oncogene. 2007 Aug 9;26(36):5300-8. Epub 2007 Feb 26. |
| PMID 17325662 |
| Expression of the rat homologue of the Drosophila fat tumour suppressor gene. |
| Ponassi M, Jacques TS, Ciani L, ffrench Constant C. |
| Mech Dev. 1999 Feb;80(2):207-12. |
| PMID 10072790 |
| The intracellular domain of the human protocadherin hFat1 interacts with Homer signalling scaffolding proteins. |
| Schreiner D, Muller K, Hofer HW. |
| FEBS Lett. 2006 Oct 2;580(22):5295-300. Epub 2006 Sep 12. |
| PMID 16979624 |
| Mammalian Fat1 cadherin regulates actin dynamics and cell-cell contact. |
| Tanoue T, Takeichi M. |
| J Cell Biol. 2004 May 24;165(4):517-28. Epub 2004 May 17. |
| PMID 15148305 |
| Clinicopathological significance of loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in China. |
| Zhang SH, Cong WM, Xian ZH, Wu MC. |
| World J Gastroenterol. 2005 May 28;11(20):3034-9. |
| PMID 15918185 |
| Citation |
| This paper should be referenced as such : |
| Chosdol, K ; Dikshit, B ; Sinha, S |
| FAT1 (FAT tumor suppressor homolog 1 (Drosophila)) |
| Atlas Genet Cytogenet Oncol Haematol. 2011;15(9):717-720. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/FAT1ID40533ch4q35.html |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Tue Aug 1 17:26:11 CEST 2017 |
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