Protocadherin FAT1 is a protein that in humans is encoded by the FAT1gene.[5][6]
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.[6]
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 [8]
The cytoplasmic tail of Fat1 has also been shown to bind the transcriptional repressor Atrophin in rat vascular smooth muscle cells [9]
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[10]
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[11]
Human FAT1 was found to bind glypican-3 (GPC3) and regulate cell migration in liver cancer cells.[13]
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.[5] 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.[14]
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.[15]
FAT1 cadherin is multiply phosphorylated on its ectodomain but phosphorylation is not catalysed by FJX1.[16] 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.[17]
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.[18] Similar splice variants have also been described for murine Fat1 where alternative splicing of the cytoplasmic tail regulated cell migration.[19]
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[20] and astrocytic tumours.[21] There are also reports of over expression of FAT1 in different cancers including DCIS breast cancer,[22] melanoma,[15] and leukaemia.[23]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ abDunne J, Hanby AM, Poulsom R, Jones TA, Sheer D, Chin WG, et al. (November 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. PMID8586420.
^Sadeqzadeh E, de Bock CE, Thorne RF (January 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. PMID23720094. S2CID27462828.
^Sadeqzadeh E, de Bock CE, O'Donnell MR, Timofeeva A, Burns GF, Thorne RF (September 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. PMID25150169. S2CID23869464.
^Nakaya K, Yamagata HD, Arita N, Nakashiro KI, Nose M, Miki T, Hamakawa H (August 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. PMID17325662. S2CID22365273.
^Kwaepila N, Burns G, Leong AS (April 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. PMID16581652. S2CID36772164.
^de Bock CE, Ardjmand A, Molloy TJ, Bone SM, Johnstone D, Campbell DM, et al. (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. PMID22116550. S2CID205194465.
Matsuyoshi N, Imamura S (June 1997). "Multiple cadherins are expressed in human fibroblasts". Biochemical and Biophysical Research Communications. 235 (2): 355–8. doi:10.1006/bbrc.1997.6707. PMID9199196.
Magg T, Schreiner D, Solis GP, Bade EG, Hofer HW (July 2005). "Processing of the human protocadherin Fat1 and translocation of its cytoplasmic domain to the nucleus". Experimental Cell Research. 307 (1): 100–8. doi:10.1016/j.yexcr.2005.03.006. PMID15922730.
Schreiner D, Müller K, Hofer HW (October 2006). "The intracellular domain of the human protocadherin hFat1 interacts with Homer signalling scaffolding proteins". FEBS Letters. 580 (22): 5295–300. doi:10.1016/j.febslet.2006.08.079. PMID16979624. S2CID10267922.
Nakaya K, Yamagata HD, Arita N, Nakashiro KI, Nose M, Miki T, Hamakawa H (August 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. PMID17325662. S2CID22365273.
