Biology:FAT1
 Generic protein structure example |
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]
Human FAT1 was found to bind glypican-3 (GPC3) and regulate cell migration in liver cancer cells.[9]
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.[10]
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.[11]
FAT1 cadherin is multiply phosphorylated on its ectodomain but phosphorylation is not catalysed by FJX1.[12] 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.[13]
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.[14] Similar splice variants have also been described for murine Fat1 where alternative splicing of the cytoplasmic tail regulated cell migration.[15]
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[16] and astrocytic tumours.[17] There are also reports of over expression of FAT1 in different cancers including DCIS breast cancer,[18] melanoma,[11] and leukaemia.[19]
References
- ↑ 1.0 1.1 "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. November 1995. doi:10.1006/geno.1995.9884. PMID 8586420.
- ↑ 2.0 2.1 "Entrez Gene: FAT FAT tumor suppressor homolog 1 (Drosophila)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2195.
- ↑ "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. May 2003. doi:10.1128/mcb.23.10.3575-3582.2003. PMID 12724416.
- ↑ "Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization". The EMBO Journal 23 (19): 3769–79. October 2004. doi:10.1038/sj.emboj.7600380. PMID 15343270.
- ↑ "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. March 2009. doi:10.1074/jbc.M809333200. PMID 19131340.
- ↑ "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. May 2009. doi:10.1073/pnas.0811691106. PMID 19439659. Bibcode: 2009PNAS..106.8579S.
- ↑ "FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation". Cellular and Molecular Life Sciences 72 (23): 4653–69. December 2015. doi:10.1007/s00018-015-1955-6. PMID 26104008.
- ↑ "Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation". Nature Genetics 45 (3): 253–61. March 2013. doi:10.1038/ng.2538. PMID 23354438.
- ↑ "Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells". Scientific Reports 11 (1): 40. January 2021. doi:10.1038/s41598-020-79524-3. PMID 33420124.
- ↑ "Sleeping giants: emerging roles for the fat cadherins in health and disease". Medicinal Research Reviews 34 (1): 190–221. January 2014. doi:10.1002/med.21286. PMID 23720094.
- ↑ 11.0 11.1 "Dual processing of FAT1 cadherin protein by human melanoma cells generates distinct protein products". The Journal of Biological Chemistry 286 (32): 28181–91. August 2011. doi:10.1074/jbc.M111.234419. PMID 21680732.
- ↑ "FAT1 cadherin is multiply phosphorylated on its ectodomain but phosphorylation is not catalysed by the four-jointed homologue". FEBS Letters 588 (18): 3511–7. September 2014. doi:10.1016/j.febslet.2014.08.014. PMID 25150169.
- ↑ "A soluble form of the giant cadherin Fat1 is released from pancreatic cancer cells by ADAM10 mediated ectodomain shedding". PLOS ONE 9 (3): e90461. 2014. doi:10.1371/journal.pone.0090461. PMID 24625754. Bibcode: 2014PLoSO...990461W.
- ↑ "An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype". PLOS Genetics 7 (8): e1002218. August 2011. doi:10.1371/journal.pgen.1002218. PMID 21876675.
- ↑ "Differentially spliced isoforms of FAT1 are asymmetrically distributed within migrating cells". The Journal of Biological Chemistry 282 (31): 22823–33. August 2007. doi:10.1074/jbc.M701758200. PMID 17500054.
- ↑ "Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array". Oncogene 26 (36): 5300–8. August 2007. doi:10.1038/sj.onc.1210330. PMID 17325662.
- ↑ "Frequent loss of heterozygosity and altered expression of the candidate tumor suppressor gene 'FAT' in human astrocytic tumors". BMC Cancer 9: 5. January 2009. doi:10.1186/1471-2407-9-5. PMID 19126244.
- ↑ "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. April 2006. doi:10.1080/00313020600559975. PMID 16581652.
- ↑ "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. May 2012. doi:10.1038/leu.2011.319. PMID 22116550.
Further reading
- "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548.
- "Identification of novel cadherins expressed in human melanoma cells". The Journal of Investigative Dermatology 108 (6): 908–13. June 1997. doi:10.1111/1523-1747.ep12292703. PMID 9182820.
- "Multiple cadherins are expressed in human fibroblasts". Biochemical and Biophysical Research Communications 235 (2): 355–8. June 1997. doi:10.1006/bbrc.1997.6707. PMID 9199196.
- "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proceedings of the National Academy of Sciences of the United States of America 97 (7): 3491–6. March 2000. doi:10.1073/pnas.97.7.3491. PMID 10737800. Bibcode: 2000PNAS...97.3491D.
- "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology 22 (6): 707–16. June 2004. doi:10.1038/nbt971. PMID 15146197.
- "Mammalian Fat1 cadherin regulates actin dynamics and cell-cell contact". The Journal of Cell Biology 165 (4): 517–28. May 2004. doi:10.1083/jcb.200403006. PMID 15148305.
- "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Research 14 (9): 1711–8. September 2004. doi:10.1101/gr.2435604. PMID 15342556.
- "Comparative genomics and diversifying selection of the clustered vertebrate protocadherin genes". Genetics 169 (4): 2179–88. April 2005. doi:10.1534/genetics.104.037606. PMID 15744052.
- "Processing of the human protocadherin Fat1 and translocation of its cytoplasmic domain to the nucleus". Experimental Cell Research 307 (1): 100–8. July 2005. doi:10.1016/j.yexcr.2005.03.006. PMID 15922730.
- "Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele". Molecular Psychiatry 11 (4): 372–83. April 2006. doi:10.1038/sj.mp.4001784. PMID 16402135.
- "The intracellular domain of the human protocadherin hFat1 interacts with Homer signalling scaffolding proteins". FEBS Letters 580 (22): 5295–300. October 2006. doi:10.1016/j.febslet.2006.08.079. PMID 16979624.
- "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. November 2006. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
- "Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array". Oncogene 26 (36): 5300–8. August 2007. doi:10.1038/sj.onc.1210330. PMID 17325662.
- "Differentially spliced isoforms of FAT1 are asymmetrically distributed within migrating cells". The Journal of Biological Chemistry 282 (31): 22823–33. August 2007. doi:10.1074/jbc.M701758200. PMID 17500054.
 |  |
