Cell-cell interactions that involve adhesion molecules are important in many developmental processes. Many adhesion molecules have been found to be conserved between Drosophila and vertebrates, indicating that the
adhesion molecules involved in tissue morphogenesis evolved long before the divergence of the arthropods and chordates. Adhesion molecules have been classified into 4 major families: the immunoglobulin
superfamily, the integrin superfamily, the selectin family, and the cadherin superfamily. Cadherins mediate homophilic,
calcium-dependent cell-cell adhesion in a wide variety of tissues and are important regulators of morphogenesis, and loss of
function may be involved in the invasion and metastasis of malignant tumors. The original or classical adherins have a highly
conserved domain structure typically including 5 extracellular, conserved repeated amino acid sequences (cadherin repeats).
The Drosophila 'fat' gene does not belong to the classical cadherin gene family yet encodes a transmembrane protein
containing 34 cadherin repeats in association with a number of other motifs Dunne et al. (1995) reported the sequence of a cDNA that was serendipitously obtained during a screen of a human
T-lymphocyte cDNA library. The full-length cDNA had the potential to encode a large protein that most resembled the
Drosophila 'fat' protein in its possession of 34 cadherin repeats and other characteristics. Therefore, they named the gene and
the gene product FAT. Analysis of the expression of FAT in fetal and adult tissues revealed that FAT mRNA is present in
many epithelial and some endothelial and smooth muscle cells.
This gene is upstream of Hippo signaling.
NCBI Summary:
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. 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 communication. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described. [provided by RefSeq, Jul 2008]
Function and cancer genomics of FAT family genes (Review). Katoh M et al. FAT1, FAT2, FAT3 and FAT4 are human homologs of Drosophila Fat, which is involved in tumor suppression and planar cell polarity (PCP). FAT1 and FAT4 undergo the first proteolytic cleavage by Furin and are predicted to undergo the second cleavage by ?-secretase to release intracellular domain (ICD). Ena/VAPS-binding to FAT1 induces actin polymerization at lamellipodia and filopodia to promote cell migration, while Scribble-binding to FAT1 induces phosphorylation and functional inhibition of YAP1 to suppress cell growth. FAT1 is repressed in oral cancer owing to homozygous deletion or epigenetic silencing and is preferentially downregulated in invasive breast cancer. On the other hand, FAT1 is upregulated in leukemia and prognosis of preB-ALL patients with FAT1 upregulation is poor. FAT4 directly interacts with MPDZ/MUPP1 to recruit membrane-associated guanylate kinase MPP5/PALS1. FAT4 is involved in the maintenance of PCP and inhibition of cell proliferation. FAT4 mRNA is repressed in breast cancer and lung cancer due to promoter hypermethylation. FAT4 gene is recurrently mutated in several types of human cancers, such as melanoma, pancreatic cancer, gastric cancer and hepatocellular carcinoma. FAT1 and FAT4 suppress tumor growth via activation of Hippo signaling, whereas FAT1 promotes tumor migration via induction of actin polymerization. FAT1 is tumor suppressive or oncogenic in a context-dependent manner, while FAT4 is tumor suppressive. Copy number aberration, translocation and point mutation of FAT1, FAT2, FAT3, FAT4, FRMD1, FRMD6, NF2, WWC1, WWC2, SAV1, STK3, STK4, MOB1A, MOB1B, LATS1, LATS2, YAP1 and WWTR1/TAZ genes should be comprehensively investigated in various types of human cancers to elucidate the mutation landscape of the FAT-Hippo signaling cascades. Because YAP1 and WWTR1 are located at the crossroads of adhesion, GPCR, RTK and stem-cell signaling network, cancer genomics of the FAT signaling cascades could be applied for diagnostics, prognostics and therapeutics in the era of personalized medicine.
Cellular localization
Plasma membrane
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Ovarian function
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Expression regulated by
LH
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Ovarian localization
Cumulus
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This gene was found in a rat ovarian cDNA library (Unigene)/// The possible FAT1-mediated apoptotic pathways in porcine cumulus cells. Wu X et al. (2016) Porcine cumulus cells are localized around oocytes and act as a specific type of granulosa that plays essential roles in the development and maturation of oocytes, the development and atresia of follicles and the development of embryos. Studies of FAT1 have demonstrated its functions in cell-cell contact, actin dynamics, and cell growth suppression. To understand whether the FAT1 gene affects the apoptosis of porcine cumulus cells and to elucidate the mechanism of this potential action, FAT1 was knocked down using RNA interference. The lack of FAT1 resulted in stable expression of CTNNB, enhanced expression of cleaved CASP3 but decreased the BCL2/BAX ratios at both the mRNA and protein levels. These results indicated that FAT1 inhibited porcine cumulus cell apoptosis via different pathways. Taken together, these data provide new insights into the mechanisms of the association between FAT1 and porcine cumulus cell apoptosis.//////////////////