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.