FAT1

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Protocadherin FAT1 is a protein that in humans is encoded by the FAT1 gene.[1][2]

Function

This gene is an ortholog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. This gene is expressed at high levels in a number of fetal epithelia. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described.[2]

The murine Fat1 knockout mouse is not embryonically lethal but pups die within 48-hours due to the abnormal fusion of foot processes of the podocytes within the kidney. These Fat1 knockout mice also showed partially penetrant but often severe midline defects including holoprosencephaly, microphthalmia-anophthalmia and in rare cases cyclopia.[3]

It has been shown that the EVH motifs in the cytoplasmic tail of mouse Fat1 interact with Ena/VASP and ablation of Fat1 by RNAi leads to decreased cell migration of rat epithelial cells [4]

The cytoplasmic tail of Fat1 has also been shown to bind the transcriptional repressor Atrophin in rat vascular smooth muscle cells [5]

At the carboxyl terminus of FAT1 lies a PDZ domain (PSD95/Dlg1/ZO-1) ligand motif (-HTEV). Zebrafish Fat1 was found to bind the protein scribble and regulate Hippo signalling[6]

Using the human SHSY5Y cell line as a model of neuronal differentiation, human FAT1 was shown to regulate Hippo kinase components with loss of FAT1 leading to nucleocytoplasmic relocation of TAZ and enhanced transcription of the Hippo target gene CTGF. The same study also showed FAT1 was able to regulate TGF-beta signaling [7]

FAT1 has been found to bind beta-catenin and regulate Wnt-signaling in colorectal cancer.[8]

Structure

The human FAT1 cadherin gene was cloned in 1995 from a human T-leukemia (T-ALL) cell line and consists of 27 exons located on chromosome 4q34–35.[1] Structurally the FAT1 protein is a single pass transmembrane protein with the extracellular portion consisting of 34 cadherin repeats, 5 EGF-like domains and a laminin-G like domain.[9]

The FAT1 protein once translated undergoes furin mediated S1 cleavage forming a non-covalent heterodimer before achieving cell surface expression although this processing is often perturbed in cancer cells which express non-cleaved FAT1 on the cell surface.[10]

FAT1 cadherin is multiply phosphorylated on its ectodomain but phosphorylation is not catalysed by FJX1.[11] The ectodomain of FAT1 can also be shed from the cell surface by the sheddase ADAM10, with release of this ectodomain a possible new biomarker in pancreatic cancer.[12]

FAT1 has also been found to undergo alternative splicing in breast cancer cells undergoing epithelial-to-mesenchymal (EMT) transition with the addition of 12 amino acids in the cytoplasmic tail.[13] Similar splice variants have also been described for murine Fat1 where alternative splicing of the cytoplasmic tail regulated cell migration.[14]

Clinical significance

Cancer

The FAT1 cadherin has been ascribed both as putative tumour suppressor or oncogene in different contexts. Loss of heterozygosity for FAT1 has been reported in primary oral carcinomas[15] and astrocytic tumours.[16] There are also reports of over expression of FAT1 in different cancers including DCIS breast cancer,[17] melanoma,[10] and leukaemia.[18]

References

  1. ↑ 1.0 1.1 Dunne J, Hanby AM, Poulsom R, Jones TA, Sheer D, Chin WG, Da SM, Zhao Q, Beverley PC, Owen MJ (Nov 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". Genomics. 30 (2): 207–23. doi:10.1006/geno.1995.9884. PMID 8586420.
  2. ↑ 2.0 2.1 "Entrez Gene: FAT FAT tumor suppressor homolog 1 (Drosophila)".
  3. ↑ Ciani L, Patel A, Allen ND, ffrench-Constant C (May 2003). "Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype". Molecular and Cellular Biology. 23 (10): 3575–82. doi:10.1128/mcb.23.10.3575-3582.2003. PMC 164754. PMID 12724416.
  4. ↑ Moeller MJ, Soofi A, Braun GS, Li X, Watzl C, Kriz W, Holzman LB (Oct 2004). "Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization". The EMBO Journal. 23 (19): 3769–79. doi:10.1038/sj.emboj.7600380. PMC 522787. PMID 15343270.
  5. ↑ Hou R, Sibinga NE (Mar 2009). "Atrophin proteins interact with the Fat1 cadherin and regulate migration and orientation in vascular smooth muscle cells". The Journal of Biological Chemistry. 284 (11): 6955–65. doi:10.1074/jbc.M809333200. PMC 2652288. PMID 19131340.
  6. ↑ Skouloudaki K, Puetz M, Simons M, Courbard JR, Boehlke C, Hartleben B, Engel C, Moeller MJ, Englert C, Bollig F, Schäfer T, Ramachandran H, Mlodzik M, Huber TB, Kuehn EW, Kim E, Kramer-Zucker A, Walz G (May 2009). "Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development". Proceedings of the National Academy of Sciences of the United States of America. 106 (21): 8579–84. doi:10.1073/pnas.0811691106. PMC 2688978. PMID 19439659.
  7. ↑ Ahmed AF, de Bock CE, Lincz LF, Pundavela J, Zouikr I, Sontag E, Hondermarck H, Thorne RF (Jun 2015). "FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation". Cellular and Molecular Life Sciences. 72: 4653–69. doi:10.1007/s00018-015-1955-6. PMID 26104008.
  8. ↑ Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan Ş, Eng S, Kannan K, Zou Y, Peng L, Banuchi VE, Paty P, Zeng Z, Vakiani E, Solit D, Singh B, Ganly I, Liau L, Cloughesy TC, Mischel PS, Mellinghoff IK, Chan TA (Mar 2013). "Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation". Nature Genetics. 45 (3): 253–61. doi:10.1038/ng.2538. PMC 3729040. PMID 23354438.
  9. ↑ Sadeqzadeh E, de Bock CE, Thorne RF (Jan 2014). "Sleeping giants: emerging roles for the fat cadherins in health and disease". Medicinal Research Reviews. 34 (1): 190–221. doi:10.1002/med.21286. PMID 23720094.
  10. ↑ 10.0 10.1 Sadeqzadeh E, de Bock CE, Zhang XD, Shipman KL, Scott NM, Song C, Yeadon T, Oliveira CS, Jin B, Hersey P, Boyd AW, Burns GF, Thorne RF (Aug 2011). "Dual processing of FAT1 cadherin protein by human melanoma cells generates distinct protein products". The Journal of Biological Chemistry. 286 (32): 28181–91. doi:10.1074/jbc.M111.234419. PMC 3151063. PMID 21680732.
  11. ↑ Sadeqzadeh E, de Bock CE, O'Donnell MR, Timofeeva A, Burns GF, Thorne RF (Sep 2014). "FAT1 cadherin is multiply phosphorylated on its ectodomain but phosphorylation is not catalysed by the four-jointed homologue". FEBS Letters. 588 (18): 3511–7. doi:10.1016/j.febslet.2014.08.014. PMID 25150169.
  12. ↑ Wojtalewicz N, Sadeqzadeh E, Weiß JV, Tehrani MM, Klein-Scory S, Hahn S, Schmiegel W, Warnken U, Schnölzer M, de Bock CE, Thorne RF, Schwarte-Waldhoff I (2014). "A soluble form of the giant cadherin Fat1 is released from pancreatic cancer cells by ADAM10 mediated ectodomain shedding". PLOS ONE. 9 (3): e90461. doi:10.1371/journal.pone.0090461. PMC 3953070. PMID 24625754.
  13. ↑ Shapiro IM, Cheng AW, Flytzanis NC, Balsamo M, Condeelis JS, Oktay MH, Burge CB, Gertler FB (Aug 2011). "An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype". PLoS Genetics. 7 (8): e1002218. doi:10.1371/journal.pgen.1002218. PMC 3158048. PMID 21876675.
  14. ↑ Braun GS, Kretzler M, Heider T, Floege J, Holzman LB, Kriz W, Moeller MJ (Aug 2007). "Differentially spliced isoforms of FAT1 are asymmetrically distributed within migrating cells". The Journal of Biological Chemistry. 282 (31): 22823–33. doi:10.1074/jbc.M701758200. PMID 17500054.
  15. ↑ Nakaya K, Yamagata HD, Arita N, Nakashiro KI, Nose M, Miki T, Hamakawa H (Aug 2007). "Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array". Oncogene. 26 (36): 5300–8. doi:10.1038/sj.onc.1210330. PMID 17325662.
  16. ↑ Chosdol K, Misra A, Puri S, Srivastava T, Chattopadhyay P, Sarkar C, Mahapatra AK, Sinha S (2009). "Frequent loss of heterozygosity and altered expression of the candidate tumor suppressor gene 'FAT' in human astrocytic tumors". BMC Cancer. 9: 5. doi:10.1186/1471-2407-9-5. PMC 2631005. PMID 19126244.
  17. ↑ Kwaepila N, Burns G, Leong AS (Apr 2006). "Immunohistological localisation of human FAT1 (hFAT) protein in 326 breast cancers. Does this adhesion molecule have a role in pathogenesis?". Pathology. 38 (2): 125–31. doi:10.1080/00313020600559975. PMID 16581652.
  18. ↑ de Bock CE, Ardjmand A, Molloy TJ, Bone SM, Johnstone D, Campbell DM, Shipman KL, Yeadon TM, Holst J, Spanevello MD, Nelmes G, Catchpoole DR, Lincz LF, Boyd AW, Burns GF, Thorne RF (May 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". Leukemia. 26 (5): 918–26. doi:10.1038/leu.2011.319. PMID 22116550.

Further reading

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