Disease relevance of FAT

• FAT1 mRNA was expressed in embryonic stem (ES) cells, neural tissues, gastric cancer, pancreatic cancer, colorectal cancer, breast cancer, lung cancer and brain tumors [1].
• FAT1 is over expressed in pre-BALL and potential prognostic marker [2]
• FAT1 provides a novel minimal residual disease marker in acute lymphoblastic leukaemia  [3]
• FAT1 is over expressed in Melanoma and undergoes incomplete cleavage [4]
• Grade 3 DCIS displayed the highest hFAT intensity compared with lower grade tumours, with significant differences between grade 1 and 3 (p = 0.015) and grade 2 and 3 (p = 0.047) [5].
• METHODS: A total of 326 cases of invasive and in situ breast cancer representing a broad spectrum of histological subtypes were immunostained with affinity-purified rabbit antibodies produced to the cytoplasmic region of hFAT using a standard avidin-biotin system [5]. 

High impact information on FAT

• In an epithelial cell wound model, FAT1 knockdown decreased recruitment of endogenous VASP to the leading edge and resulted in impairment of lamellipodial dynamics, failure of polarization, and an attenuation of cell migration [6].
• In another step, the cleavage product was released to the cytosol and was also found in a low speed pellet fraction, in accordance with the nuclear localization of the cytoplasmic domain of hFat1 [7].
• Fatty acid bing protein 4 (FABP4) plays a key role in fat regulation in mammals and is a strong positional candidate gene for the FAT1 quantitative trait locus located on porcine chromosome 4 [8].
• To both improve the comparative map of the entire SSC4 and to define the specific human chromosome region with conserved synteny to FAT1, we have now mapped 103 loci to pig Chromosome 4 using a combination of radiation hybrid and linkage mapping [9].
• Furthermore, a haplotype analysis suggests that there is genetic heterogeneity at the FAT1 locus within the Landrace breed [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 [4]
• 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 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  [13]

Biological context of FAT

• Further mapping has refined the FAT1 QTL to a region with conserved synteny to both human Chromosomes 1 and 8 [9].
• RESULTS: Progeny-testing was used to determine the QTL genotype for 10 backcross sires being heterozygous for different parts of the broad FAT1 region [14].
• Refined localization of the FAT1 quantitative trait locus on pig chromosome 4 by marker-assisted backcrossing [14].
• The flanking markers for the small region are RXRG and SDHC and the orthologous region of FAT1 in the human genome is located on HSA1q23.3 and harbors approximately 20 genes [14].

Analytical, diagnostic and therapeutic context of FAT

• With the sample sizes used in the present study we cannot with great confidence determine whether these smaller effects in some sires are due to chance deviations, epistatic interactions or whether FAT1 is composed of two or more QTLs, each one with a smaller phenotypic effect [14].

References