FAT1

FAT1 is a giant atypical protocadherin that functions as a multifunctional tumor suppressor and signaling scaffold, restraining cell proliferation, EMT, and angiogenesis through convergent regulation of the Hippo, Wnt/β-catenin, and MAPK pathways. FAT1 assembles a Hippo signaling complex by scaffolding TAOK kinases to activate LATS1/2, thereby phosphorylating and inactivating YAP1/TAZ; in endothelial cells it additionally recruits the E3 ubiquitin ligase MIB2 to ubiquitinate and degrade YAP/TAZ, limiting angiogenesis (PMID:29985391, PMID:37031213, PMID:30537512). Its intracellular domain, released by constitutive furin-mediated proteolytic processing, sequesters β-catenin from the nucleus to suppress Wnt target gene transcription, localizes to mitochondria where it restrains respiratory complex I/II activity and ATP production, and interacts with caspase-8 to prevent DISC assembly and death-receptor-mediated apoptosis (PMID:16682528, PMID:27828948, PMID:24442637, PMID:21680732). Loss of FAT1 activates a CAMK2–CD44–SRC axis driving YAP1 nuclear translocation and a hybrid EMT state with enhanced tumor stemness and metastasis (PMID:33328637).

1. 2005 Medium

   Establishing that FAT1 undergoes regulated intramembrane proteolysis answered how a giant transmembrane cadherin could signal intracellularly: sequential cleavages release a cytoplasmic domain that translocates to the nucleus via a juxtamembrane NLS.

   Evidence EGFP-fusion constructs and deletion mutants in HEK293/HeLa cells with subcellular fractionation

   PMID:15922730

   Open questions at the time

   • Identity of the second (intramembrane) protease unresolved
   • Nuclear function of the released IC domain not determined
   • Single-lab observation
2. 2006 High

   Identifying β-catenin as a direct binding partner of the FAT1 intracellular domain established FAT1 as a negative regulator of Wnt signaling, explaining how FAT1 loss increases cyclin D1 expression and proliferation.

   Evidence Co-immunoprecipitation, nuclear fractionation, and knockdown in vascular smooth muscle cells with luciferase transcription assays

   PMID:16682528

   Open questions at the time

   • Stoichiometry and affinity of FAT1-IC/β-catenin interaction unknown
   • Whether β-catenin sequestration is the dominant anti-proliferative mechanism in vivo unclear
3. 2011 High

   Demonstrating that furin is the proprotein convertase constitutively cleaving FAT1 at the cell surface resolved the protease identity for the first processing step and revealed aberrant processing in melanoma.

   Evidence Furin inhibitor treatment, Western blotting, and subcellular fractionation in keratinocytes and melanoma cells

   PMID:21680732

   Open questions at the time

   • Functional significance of melanoma-specific 65-kDa fragment uncharacterized
   • Furin cleavage site not mapped at residue resolution
4. 2014 High

   Discovery that FAT1 physically sequesters caspase-8 away from the DISC revealed an unexpected anti-apoptotic role, explaining why FAT1 loss sensitizes glioblastoma cells to death-receptor-induced apoptosis.

   Evidence Genome-wide siRNA screen, reciprocal Co-IP, DISC immunoprecipitation, and CRISPR knockout in glioblastoma cells

   PMID:24442637

   Open questions at the time

   • Structural basis of FAT1–caspase-8 interaction unknown
   • Whether this anti-apoptotic function operates in non-cancer cell types not tested
5. 2016 High

   Localization of FAT1-IC fragments to mitochondria and their direct suppression of respiratory complexes I and II established FAT1 as a metabolic brake, linking it to control of proliferation via ATP and aspartate biosynthesis.

   Evidence Subcellular fractionation, Co-IP with mitochondrial inner membrane proteins, oximetry, complex activity assays, and Fat1 KO mouse vascular injury model with mitochondria-targeted rescue

   PMID:27828948

   Open questions at the time

   • Mechanism by which FAT1-IC inhibits supercomplex assembly not structurally resolved
   • Generality beyond vascular smooth muscle cells not fully explored
6. 2018 High

   Identification of FAT1 as a scaffold assembling TAOKs and core Hippo kinases into a signalome complex that activates LATS1/2 to phosphorylate YAP1 provided the first direct biochemical link between FAT1 and the Hippo pathway, explaining the tumor-suppressive phenotype of FAT1 loss across cancers.

   Evidence Reciprocal Co-IP, kinase activity assays, pan-cancer genomics, and FAT1 loss-of-function in HNSCC cell lines

   PMID:29985391 PMID:30537512

   Open questions at the time

   • Precise binding interfaces between FAT1-IC and TAOK/LATS not mapped
   • Whether FAT1 scaffolding is regulated by upstream signals unknown
7. 2020 High

   Genetic deletion of Fat1 in mouse skin and lung tumors revealed a CAMK2–CD44–SRC axis driving YAP1 nuclear entry and a parallel EZH2-inactivation/SOX2-upregulation circuit, establishing that FAT1 loss induces a hybrid EMT state with enhanced stemness and metastasis.

   Evidence Fat1 conditional KO mice, multi-omic transcriptional/chromatin/proteomic profiling, and mechanistic epistasis in SCC and lung tumor models

   PMID:33328637

   Open questions at the time

   • Whether CAMK2 activation is a direct or indirect consequence of FAT1 loss not resolved
   • Relative contribution of YAP1 vs. SOX2 arm to metastasis not fully dissected
8. 2022 Medium

   ChIP showing β-catenin binding the ABCC3 promoter upon FAT1 knockdown linked β-catenin de-repression to cisplatin resistance and stemness in esophageal SCC, providing a clinically relevant downstream effector of FAT1-mediated β-catenin control.

   Evidence siRNA knockdown, nuclear fractionation, ChIP, luciferase assays, and drug efflux/sphere-forming assays in ESCC cells

   PMID:35606602

   Open questions at the time

   • Single-lab finding in one cancer type
   • Whether ABCC3 is sufficient or necessary for chemoresistance upon FAT1 loss not genetically tested
9. 2022 High

   Identification of FAT1 as a target antigen in hematopoietic stem cell transplant-associated membranous nephropathy revealed a disease-relevant autoimmune context for FAT1, with anti-FAT1 IgG4 deposited along glomerular basement membranes.

   Evidence Laser microdissection/MS of glomeruli, IHC/IF, and Western blot of eluates and serum in two independent patient cohorts

   PMID:35321939

   Open questions at the time

   • Whether anti-FAT1 antibodies are pathogenic or epiphenomenal not demonstrated
   • Epitope(s) on FAT1 recognized by autoantibodies not mapped
10. 2023 High

    Discovery that FAT1 recruits the E3 ligase MIB2 to ubiquitinate YAP/TAZ for proteasomal degradation in endothelial cells provided a Hippo-kinase-independent mechanism of YAP/TAZ suppression and linked FAT1 to angiogenesis control.

    Evidence Co-IP identifying MIB2, ubiquitination assays, endothelial-specific FAT1 and MIB2 KO in vitro and in vivo angiogenesis models

    PMID:37031213

    Open questions at the time

    • Whether MIB2-mediated degradation operates concurrently with LATS-dependent phosphorylation not addressed
    • Structural basis of FAT1–MIB2 interaction unknown

• A unified structural and quantitative model integrating FAT1's simultaneous roles as Hippo scaffold, β-catenin sequestrant, mitochondrial brake, caspase-8 inhibitor, and MIB2 recruiter — and how these activities are partitioned across its proteolytic fragments and cell types — remains to be established.
• No high-resolution structure of FAT1 intracellular domain or its complexes
• How FAT1-IC is partitioned among mitochondrial, nuclear, and cytoplasmic pools is not quantified
• Whether different proteolytic fragments mediate distinct signaling arms has not been tested with separation-of-function mutants