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FAT1, FAT2, FAT3 and FAT4 are human homologs of Drosophila Fat, which isinvolved in tumor suppression and planar cell polarity (PCP). FAT1 and FAT4 undergothe first proteolytic cleavage by Furin and are predicted to undergo the secondcleavage by γ‑secretase to release intracellular domain (ICD). Ena/VAPS‑bindingto FAT1 induces actin polymerization at lamellipodia and filopodia to promotecell migration, while Scribble‑binding to FAT1 induces phosphorylation and functionalinhibition of YAP1 to suppress cell growth. FAT1 is repressed in oral cancer owingto homozygous deletion or epigenetic silencing and is preferentially downregulatedin invasive breast cancer. On the other hand, FAT1 is upregulated in leukemiaand prognosis of preB‑ALL patients with FAT1 upregulation is poor. FAT4 directlyinteracts 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 FAT4suppress tumor growth via activation of Hippo signaling, whereas FAT1 promotestumor migration via induction of actin polymerization. FAT1 is tumor suppressiveor oncogenic in a context‑dependent manner, while FAT4 is tumor suppressive. Copynumber aberration, translocation and point mutation of FAT1, FAT2, FAT3, FAT4,FRMD1, FRMD6, NF2, WWC1, WWC2, SAV1, STK3, STK4, MOB1A, MOB1B, LATS1, LATS2, YAP1and WWTR1/TAZ genes should be comprehensively investigated in various types ofhuman 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 andstem‑cell signaling network, cancer genomics of the FAT signaling cascades couldbe applied for diagnostics, prognostics and therapeutics in the era of personalizedmedicine.

Function and cancer genomics of FAT family genes