Function and cancer genomics of FAT family genes (review).
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 γ‑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.
Division of Integrative Omics and Bioinformatics, National Cancer Center, Tokyo 104-0045, Japan. mkatoh-kkr@umin.ac.jp
Masaru
M
Katoh
D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism*; D023281:Genomics; D006801:Humans; D005810:Multigene Family; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
D015820:Cadherins; C502403:FAT1 protein, human; D025521:Tumor Suppressor Proteins