Affinage

FAT4

Protocadherin Fat 4 · UniProt Q6V0I7

Length
4981 aa
Mass
542.7 kDa
Annotated
2026-06-09
56 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAT4 is a large transmembrane atypical cadherin that functions as a planar cell polarity (PCP) receptor governing oriented cell division, tissue growth, and progenitor behavior across multiple developing organs including kidney, ear, skeleton, heart, gut, brain, and lymphatic vasculature (PMID:18604206, PMID:21303848, PMID:24056717). It acts as the receptor for the ligand DCHS1 (Dachsous1, partially redundant with DCHS2), forming high-affinity heterophilic complexes whose structural basis lies in an extended binding interface across EC domains 1–4 stabilized by an extensive salt-bridge network (PMID:36797229); FAT4 and DCHS1 are expressed in complementary gradients and accumulate as polarized complexes at cell boundaries through a threshold-like, self-stabilizing feedback mechanism (PMID:28826487, PMID:26116666), with the FAT4 intracellular domain driving trans-endocytosis of DCHS1 and actin-dependent boundary accumulation (PMID:39955614). FAT4 acts upstream of the Hippo pathway largely through non-canonical routes: it restrains YAP nuclear translocation by directly binding YAP and by sequestering the intermediate Amotl1 in the cytoplasm, independent of canonical LATS1/2 phosphorylation, thereby limiting cardiomyocyte, neural progenitor, and osteoprogenitor proliferation (PMID:28239148, PMID:42023818, PMID:24056717, PMID:31358536), while in several developmental and cancer contexts it also regulates progenitor self-renewal and cell proliferation entirely independently of YAP/TAZ (PMID:26116661, PMID:27381226). FAT4 additionally tunes RET–GFRA1–GDNF receptor tyrosine kinase signaling non-autonomously through its extracellular cadherin repeats during ureteric budding (PMID:30853441), promotes β-catenin destruction-complex-mediated degradation (PMID:37658376), and represses Fjx1 (PMID:18604206). FAT4 expression is controlled upstream by Hedgehog effector GLI2 and by GATA2 in lymphatic endothelium (PMID:32155439, PMID:32182215), and FAT4 protein abundance is set post-translationally by USP51-mediated stabilization and UBE4B-mediated ubiquitination and degradation (PMID:31217854, PMID:40701960). Loss-of-function FAT4 mutations cause periventricular neuronal heterotopia in humans (PMID:24056717), and FAT4 behaves as a tumor suppressor whose loss activates YAP and Wnt/β-catenin signaling (PMID:26575609, PMID:37658376).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2008 High

    Established that vertebrate Fat4 is a PCP signaling component, answering whether Drosophila Fat signaling is conserved and linking it to oriented cell division and tissue morphogenesis.

    Evidence Fat4 knockout mice with genetic epistasis against Vangl2 and Fjx1 and gene expression analysis in kidney

    PMID:18604206

    Open questions at the time
    • Molecular ligand of Fat4 not yet identified
    • Downstream effector pathway not defined
    • Mechanism of Fjx1 repression unknown
  2. 2011 High

    Identified DCHS1 as the Fat4 ligand-receptor partner, answering what molecule FAT4 engages and showing reciprocal protein-level dependence across many organs.

    Evidence Dchs1 knockout, Fat4/Dchs1 double mutant analysis and reciprocal antibody staining in mice

    PMID:21303848

    Open questions at the time
    • Direct physical binding not biochemically demonstrated
    • Structural basis of interaction unknown
    • Intracellular signaling output not defined
  3. 2013 High

    Placed FAT4 upstream of YAP in the Hippo pathway during neurogenesis and tied FAT4 mutation to a human brain malformation.

    Evidence Mouse neuroepithelium knockdown with concurrent Yap rescue and human mutation identification

    PMID:24056717

    Open questions at the time
    • Mechanism connecting FAT4 to YAP not resolved
    • Canonical vs non-canonical Hippo link unclear
  4. 2014 High

    Showed PCP is encoded by graded Fat4/Dchs1 expression and operates on an axis orthogonal to Frizzled-PCP, clarifying how directional information is established.

    Evidence Conditional and mosaic knockout mice with live imaging of facial branchiomotor neuron migration

    PMID:24998526

    Open questions at the time
    • Molecular readout of gradient sensing unknown
    • Intracellular polarity machinery not identified
  5. 2015 High

    Resolved that FAT4 controls progenitor self-renewal non-autonomously via stromal-to-mesenchyme signaling, and notably can do so independently of YAP, revealing a YAP-independent branch.

    Evidence Tissue-specific conditional knockouts, Six2;Fat4 and Yap epistasis, and polarized Dchs1 localization in genetic mosaics

    PMID:26116661 PMID:26116666

    Open questions at the time
    • Identity of the YAP-independent effector unknown
    • How stromal FAT4 transmits a signal across cell layers unresolved
  6. 2015 Low

    Implicated FAT4 as a tumor suppressor acting through Wnt/β-catenin, extending its role beyond development to cancer.

    Evidence FAT4 siRNA knockdown in gastric cancer cells with pathway western blots and xenografts

    PMID:26633557

    Open questions at the time
    • Pathway activity inferred from western blot without direct binding evidence
    • No mechanism linking FAT4 to the β-catenin destruction complex shown
  7. 2016 Medium

    Distinguished FAT4 functional outputs that are YAP/TAZ-independent and proposed cis-heterodimerization with FAT1, broadening the interactor repertoire.

    Evidence Fat4/Fat1 and Fat4;Yap/Fat4;Taz double mutants, proteomics, and in vitro binding assays

    PMID:26209645 PMID:27145737 PMID:27381226

    Open questions at the time
    • FAT1-FAT4 cis-heterodimer not confirmed in vivo
    • Effectors of the YAP/TAZ-independent branch not identified
  8. 2017 High

    Defined a non-canonical Hippo mechanism whereby FAT4 sequesters Amotl1 in the cytoplasm to restrict proliferation, identifying a mammalian intermediate downstream of FAT4.

    Evidence Fat4 mutant myocardium with nuclear fractionation, co-localization, and YAP transcriptional assays

    PMID:28239148

    Open questions at the time
    • Direct FAT4-Amotl1 binding not structurally defined
    • How extracellular FAT4 engagement controls Amotl1 localization unclear
  9. 2017 High

    Provided biophysical evidence that Fat4-Dchs1 complexes self-stabilize and polarize, establishing the molecular feedback underlying boundary accumulation.

    Evidence Synthetic reconstitution of human Fat4/Ds1 in mammalian cells with live imaging and FRAP, plus lymphatic valve mutant analysis

    PMID:28705793 PMID:28826487

    Open questions at the time
    • Molecular determinant of slowed complex dynamics not defined
    • Link from complex stability to downstream signaling unresolved
  10. 2019 High

    Identified RET as a direct FAT4 extracellular partner, showing FAT4 fine-tunes RET-GFRA1-GDNF receptor tyrosine kinase signaling beyond PCP/Hippo.

    Evidence Co-IP of FAT4-RET, conditional knockouts, and Gdnf heterozygous genetic rescue in kidney

    PMID:30853441

    Open questions at the time
    • Structural basis of FAT4-RET interaction unknown
    • Whether DCHS1 engagement modulates RET binding untested
  11. 2019 High

    Tied FAT4 protein stability to deubiquitination and linked FAT4 loss to differential YAP/TAZ-Runx2 transcriptional output, adding post-translational and tissue-specific regulatory layers.

    Evidence Co-IP of FAT4-USP51 with bidirectional stability assays in endometrial cancer, and Dchs1/Fat4 mutants with Tead/Runx2 reporters in osteoblasts

    PMID:30832706 PMID:31217854 PMID:31358536

    Open questions at the time
    • USP51 deubiquitination site on FAT4 not mapped
    • PI3K-AKT/mTOR link to FAT4 inferred only from western blot
  12. 2020 High

    Placed FAT4 transcriptionally downstream of Hedgehog/GLI2 and GATA2, defining how FAT4 expression is induced in gut and lymphatic contexts.

    Evidence GLI2 targetome and Fat4/Dchs1/Vangl2 mutants in gut; cell-autonomous Fat4 conditional knockout and GATA2 target validation in lymphatics

    PMID:32155439 PMID:32182215

    Open questions at the time
    • Direct GLI2/GATA2 binding to the FAT4 locus in each tissue not all mapped
    • How flow is transduced to FAT4-dependent polarity unresolved
  13. 2023 High

    Delivered the atomic structure of the Fat4-Dchs1 interface, explaining the unusually high heterophilic affinity and a route for phosphoregulation.

    Evidence Co-crystal structure of human Fat4 EC1-4 with Dchs1 and biophysical affinity measurements

    PMID:36797229

    Open questions at the time
    • Functional impact of extracellular phosphorylation on binding not tested in vivo
    • Full-length complex architecture beyond EC1-4 unknown
  14. 2023 Medium

    Mechanistically connected FAT4 to β-catenin destruction-complex-mediated degradation and a downstream immune-evasion axis in cancer.

    Evidence FAT4 overexpression with Co-IP of FAT4-β-catenin and PD-L1 glycosylation/ubiquitination assays in cervical cancer xenografts

    PMID:37658376

    Open questions at the time
    • Direct FAT4-β-catenin binding interface not mapped
    • Single lab, requires independent confirmation
  15. 2024 Medium

    Demonstrated FAT4 can participate in IL-32-driven canonical Hippo activation via MST1/2, contrasting with its non-canonical roles elsewhere.

    Evidence IP-MS identification of IL-32-FAT4-MST1/2 complex and FAT4 knockdown in nucleus pulposus cells with a rat model

    PMID:39178518

    Open questions at the time
    • Direct FAT4-MST1/2 binding not validated reciprocally
    • Reconciliation with non-canonical FAT4-Hippo activity unresolved
  16. 2025 Medium

    Defined the FAT4 intracellular domain as the driver of Dchs1 trans-endocytosis and actin-dependent boundary accumulation, explaining how the receptor enforces polarized complex distribution.

    Evidence Quantitative live imaging of Fat4 ICD deletion mutants with FRAP and actin polymerization inhibition; plus UBE4B Co-IP/proteomics establishing FAT4 ubiquitination and degradation

    PMID:39955614 PMID:40701960

    Open questions at the time
    • ICD motifs mediating endocytosis not mapped
    • UBE4B ubiquitination sites on FAT4 undefined
  17. 2026 Medium

    Showed FAT4 directly binds YAP to retain it in the cytoplasm independently of LATS1/2 phosphorylation, consolidating a direct non-canonical Hippo control mechanism.

    Evidence Co-IP of FAT4-YAP, knockdown, nuclear fractionation in zebrafish and mouse models

    PMID:42023818

    Open questions at the time
    • FAT4-YAP binding interface not mapped
    • How a transmembrane cadherin physically contacts cytoplasmic YAP unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single extracellular Fat4-Dchs1 engagement event is transduced into the diverse intracellular outputs—non-canonical YAP/Amotl1 sequestration, YAP/TAZ-independent proliferation control, RET modulation, and β-catenin degradation—remains unresolved.
  • No unified model linking ligand binding to the multiple downstream branches
  • Tissue determinants selecting canonical vs non-canonical Hippo output unknown
  • Direct intracellular interaction interfaces (YAP, Amotl1, β-catenin) not structurally defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
AMOTL1CTNNB1DCHS1FAT1RETUBE4BUSP51YAP1
Complex memberships
Fat4-Dchs1 heterophilic complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Fat4 is required for oriented cell divisions and tubule elongation during kidney development; loss of Fat4 disrupts planar cell polarity (PCP) signaling, leading to cystic kidney disease. Fat4 genetically interacts with the PCP genes Vangl2 and Fjx1 in cyst formation, and Fat4 represses Fjx1 expression, indicating conservation of Fat signaling from Drosophila to vertebrates. Genetic loss-of-function (Fat4 knockout mice), genetic epistasis with Vangl2 and Fjx1, gene expression analysis Nature genetics High 18604206
2011 Dchs1 and Fat4 function as a ligand-receptor pair during murine development; they are predominantly expressed in mesenchymal cells, and mutation of either gene increases protein staining for the other. They regulate planar cell polarity, kidney growth and branching, and cell survival in multiple organs including the ear, kidney, skeleton, intestine, heart and lung. Gene-targeted mutation (Dchs1 knockout mice), comparison with Fat4 mutants, double mutant analysis, antibody staining Development (Cambridge, England) High 21303848
2013 Mutations in FAT4 (and its ligand DCHS1) lead to periventricular neuronal heterotopia; reducing Dchs1 or Fat4 in mouse neuroepithelium increased progenitor cell numbers and reduced differentiation into neurons. These effects were countered by concurrent knockdown of Yap, placing FAT4 upstream of YAP in the Hippo signaling pathway during neurogenesis. Loss-of-function in mouse embryonic neuroepithelium (knockdown), Yap concurrent knockdown (epistasis), human genetic mutation identification Nature genetics High 24056717
2014 Fat4 and Dchs1 are expressed in complementary gradients and are required intrinsically within facial branchiomotor (FBM) neurons and extrinsically within the neuroepithelium for collective tangential neuronal migration and PCP. Fat-PCP and Fz-PCP regulate FBM neuron migration along orthogonal axes. Disruption of Dchs1 gradients by mosaic inactivation alters FBM neuron polarity and migration, implying that PCP is regulated via gradients of Fat4 and Dchs1 expression. Conditional and mosaic knockout mice, live imaging, PCP analysis, genetic epistasis Current biology : CB High 24998526
2015 FAT4 acts non-autonomously in the renal stroma to control nephron progenitors. Loss of Yap from cap mesenchyme (CM) in Fat4-null mice does not reduce the expanded CM, indicating FAT4 regulates the CM independently of YAP. Excess progenitors in Fat4 mutants are dependent on Six2. Dchs1 and its paralogue Dchs2 function partially redundantly to regulate nephron progenitor numbers. FAT4 in the stroma binds to DCHS1/2 in the CM to restrict progenitor self-renewal. Tissue-specific conditional knockouts, Six2−/−;Fat4−/− double mutants, electron microscopy, gene expression analysis Development (Cambridge, England) High 26116661
2015 Fat4 and Dchs1 are implicated in signaling between stromal and cap mesenchyme cell layers in the kidney; Dchs1 protein is polarized within cap mesenchyme cells, accumulating at the interface with stromal cells, consistent with direct interaction with a stromal protein (Fat4). Dchs1 acts as a Fat4 receptor for stromal signaling essential for kidney development. Dchs1 conditional knockout mice, antibody staining of genetic mosaics revealing polarized Dchs1 protein localization, phenotypic comparison with Fat4 mutants Development (Cambridge, England) High 26116666
2015 Fat1 and Fat4 interact genetically to regulate neural tube closure, neural progenitor proliferation, and apical constriction. Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins. In vitro data suggest that Fat1 and Fat4 form cis-heterodimers, providing a mechanism for bringing together their diverse interactors. Fat1 and Fat4 mouse knockouts, in utero electroporation, proteomic analysis, in vitro binding assays Development (Cambridge, England) Medium 26209645
2016 Dchs1-Fat4 PCP pathway controls cell orientation in the early skeletal condensation to define the shape and dimensions of the mouse sternum. This involves cell intercalation along differential Dchs1-Fat4 activity. Fat4 and Dchs1 establish polarized cell behavior intrinsically within the mesenchyme. Fat4 and Dchs1 knockout mice, cell orientation analysis in skeletal condensations Nature communications Medium 27145737
2016 Fat4 and Dchs1 regulate vertebral development through control of cell proliferation in the early sclerotome, independently of Yap and Taz; analysis of Fat4;Yap and Fat4;Taz double mutants and expression of transcriptional target Ctgf indicates this is a Yap/Taz-independent mechanism of Fat4-Dchs1 signaling. Fat4−/− and Dchs1−/− knockout mice, Fat4;Yap and Fat4;Taz double mutants, Ctgf expression analysis Development (Cambridge, England) Medium 27381226
2016 Fat4 suppression leads to increased phosphorylated Yap and nuclear accumulation of Yap in gastric cancer cells, promoting proliferation, migration, and cell cycle progression. Re-expression of full-length Fat4 decreases phosphorylated Yap and inhibits cell cycle progression. Fat4 reduction also leads to accumulation of cytoplasmic β-catenin via loss of restraint on cytoplasmic Yap. Fat4-shRNA knockdown, Fat4 overexpression, western blotting, cell proliferation and migration assays Cancer biology & therapy Medium 26575609
2017 In the mouse heart, Fat4 modulates Hippo signaling to restrict cardiomyocyte growth and proliferation. Fat4 is not required for canonical activation of Hippo kinases but sequesters Amotl1 out of the nucleus; nuclear translocation of Amotl1 is accompanied by Yap1 to promote cardiomyocyte proliferation. Amotl1 is identified as a mammalian intermediate for non-canonical Hippo signaling downstream of Fat4. Fat4 mutant mouse myocardium analysis, Yap1 transcriptional activity assay, nuclear fractionation, co-localization studies Nature communications High 28239148
2017 Dachsous1-Fat4 signaling is required specifically for lymphatic valve morphogenesis; valve endothelial cells are disoriented and fail to form proper valve leaflets in Fat4 or Dachsous1 mutant mice. Dachsous1 is polarized to membrane protrusions and cellular junctions of valve endothelial cells in vivo and in vitro. Fat4 and Dachsous1 mutant mice, Lifeact-GFP imaging of actin dynamics, in vitro and in vivo immunostaining of Dchs1 localization Arteriosclerosis, thrombosis, and vascular biology Medium 28705793
2017 Fat4-Ds1 complexes accumulate on cell boundaries in a threshold-like manner and exhibit dramatically slower dynamics than unbound Fat4 and Ds1, providing evidence for a localized feedback mechanism based on enhanced stability of Fat4-Ds1 complexes. Co-expression of Fat4 and Ds1 in the same cells is sufficient to induce polarization of Fat4-Ds1 complexes. Synthetic biology platform in mammalian cells expressing human Fat4 and Ds1, live-cell imaging of complex dynamics and FRAP eLife High 28826487
2019 FAT4 interacts with RET through extracellular cadherin repeats and perturbs the assembly of the RET-GFRA1-GDNF complex, thereby reducing RET signaling. Loss of Fat4 causes abnormal ureteric budding and excessive RET signaling; removal of one copy of the RET ligand Gdnf rescues Fat4−/− kidney development. FAT4 acts non-autonomously to regulate RET signaling. Fat4 knockout mice, conditional knockout analyses, co-immunoprecipitation of FAT4-RET interaction, Gdnf heterozygous rescue epistasis Developmental cell High 30853441
2019 FAT4 regulates EMT and autophagy in colorectal cancer cells in part via the PI3K-AKT/mTOR and PI3K-AKT/GSK-3β signaling pathways; FAT4 promotes autophagy and inhibits EMT through PI3K activity regulation. FAT4 overexpression and knockdown, western blotting for PI3K/AKT pathway components, transwell assays, xenograft model Journal of experimental & clinical cancer research : CR Low 30832706
2019 Dchs1-Fat4 signaling is essential for osteoblast differentiation; loss of Dchs1-Fat4 signaling increases Yap-Tead activity in osteoprogenitors, and Yap is required for proliferation in these cells. Taz is expressed in more-committed Runx2-expressing osteoblasts, and Taz-Tead activity is unaffected in Dchs1/Fat4 mutants. Yap and Taz differentially regulate Runx2 transcriptional activity, and the activity of Yap-Runx2 and Taz-Runx2 complexes is altered in Dchs1/Fat4 mutant osteoblasts. Dchs1 and Fat4 mutant mice, YAP and TAZ knockouts, reporter assays for Tead and Runx2 activity Development (Cambridge, England) High 31358536
2019 FAT4 silencing in endometrial cancer decreases phosphorylation of LATS1/2 and YAP while increasing YAP nuclear translocation, consistent with Hippo pathway suppression. Co-immunoprecipitation confirmed direct binding of FAT4 and the deubiquitinating enzyme USP51. USP51 knockdown decreases FAT4 protein level while USP51 overexpression increases FAT4 protein level, indicating USP51 is required for FAT4 stability. FAT4 knockdown and overexpression, shRNA for USP51, PCR array, co-immunoprecipitation, western blotting American journal of translational research Medium 31217854
2020 GLI2 (a Hedgehog transcriptional effector) directly activates atypical cadherin and PCP genes including Fat4; Fat4 and Dchs1 are critical for villus formation in gut development. The Fat4-Dchs1 axis acts in parallel to the core-Vangl2 PCP axis to control mesenchymal cell clustering. WNT5A guides oriented cell migration of PDGFRα+ mesenchymal cells via PCP. GLI2 targetome analysis, Fat4 and Dchs1 knockout mice, Vangl2 PCP-mutant mice, genetic interaction studies, live light-sheet fluorescence microscopy of cultured PDGFRα+ cells Developmental cell High 32155439
2020 FAT4 functions in a lymphatic endothelial cell-autonomous manner to control cell polarity in response to flow and is required for lymphatic vessel morphogenesis. FAT4 is a target gene of GATA2, a transcriptional regulator of lymphatic vascular development. Fat4 conditional knockout (cell-autonomous analysis), flow-dependent polarity assays, GATA2 target gene identification The Journal of clinical investigation Medium 32182215
2023 The co-crystal structure of human Fat4 (EC domains 1-4) and Dachsous1 (Dchs1) establishes the molecular basis for Fat-Dachsous heterophilic interactions. The binding interface is extended along EC domains 1-4 of each protein. Fat4-Dchs1 affinity is among the highest reported for cadherin superfamily members, attributed to an extensive network of salt bridges not present in structurally similar protocadherin homodimers. Extracellular phosphorylation modifications may directly modulate Fat-Dachsous binding by introducing charged contacts across the interface. Co-crystal structure determination, biophysical affinity measurements, structural modeling of phosphorylation effects Nature communications High 36797229
2023 FAT4 overexpression binds β-catenin and antagonizes its nuclear localization, promoting phosphorylation and degradation of β-catenin by the destruction complex (AXIN1, APC, GSK3β, CK1). This suppresses STT3A-mediated PD-L1 N-glycosylation, causing PD-L1 ER accumulation and polyubiquitination-dependent degradation, thereby reducing immune evasion in cervical cancer. FAT4 overexpression, Co-IP of FAT4-β-catenin interaction, functional assays for PD-L1 glycosylation and ubiquitination, immunodeficient and immunocompetent xenograft models Journal of experimental & clinical cancer research : CR Medium 37658376
2024 IL-32 interacts with FAT4 and MST1/2 proteins (identified by immunoprecipitation and mass spectrometry); elevation of IL-32 enhances its interactions with FAT4 and MST1/2, prompting MST1/2 phosphorylation and activating the Hippo/YAP signaling pathway, causing matrix metabolism disorder in nucleus pulposus cells. Immunoprecipitation and mass spectrometry, lentiviral FAT4 knockdown, western blotting for MST1/2 phosphorylation and YAP, rat in vivo model International immunopharmacology Medium 39178518
2025 The intracellular domain (ICD) of Fat4 is required for trans-endocytosis of Dchs1 into Fat4-expressing cells and for boundary accumulation of Fat4/Dchs1 complexes. The Fat4 ICD controls the internalization rate of Fat4/Dchs1 complexes. Actin polymerization is required for accumulation of Fat4/Dchs1 complexes at boundaries. Quantitative live imaging of Fat4 ICD deletion mutants, FRAP, actin polymerization inhibition, mammalian cell expression system Biophysical journal Medium 39955614
2025 UBE4B directly binds to and ubiquitinates FAT4, leading to its proteasomal degradation. Tandem Mass Tag (TMT) proteomics revealed FAT4 as a downstream target of UBE4B; UBE4B inhibits autophagy in gastric cancer cells by mediating FAT4 ubiquitination and degradation. Co-IP, TMT quantitative proteomics, western blot, transmission electron microscopy, UBE4B knockdown/overexpression Cell death & disease Medium 40701960
2026 FAT4 directly interacts with YAP (shown by co-immunoprecipitation) and retains YAP in the cytoplasm, blocking its nuclear translocation, independently of the canonical Hippo phosphorylation cascade (LATS1/2-mediated). FAT4 knockdown promotes nuclear translocation of YAP without altering canonical phosphorylation. Co-immunoprecipitation of FAT4-YAP, FAT4 knockdown, nuclear fractionation, zebrafish and mouse in vivo models Cancer science Medium 42023818
2015 FAT4 functions as a tumor suppressor in gastric cancer by modulating Wnt/β-catenin signaling; knockdown of FAT4 promotes growth and invasion via activation of Wnt/β-catenin signaling and induces EMT. FAT4 siRNA knockdown in gastric cancer cell lines, western blotting for Wnt/β-catenin pathway components, xenograft model in vivo British journal of cancer Low 26633557

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nature genetics 415 18604206
2013 Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nature genetics 215 24056717
2011 Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. Development (Cambridge, England) 168 21303848
2019 FAT4 regulates the EMT and autophagy in colorectal cancer cells in part via the PI3K-AKT signaling axis. Journal of experimental & clinical cancer research : CR 156 30832706
2014 Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Human genetics 113 24913602
2009 Identification of Fat4 as a candidate tumor suppressor gene in breast cancers. International journal of cancer 92 19048595
2017 Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth. Nature communications 83 28239148
2015 Stromal Fat4 acts non-autonomously with Dchs1/2 to restrict the nephron progenitor pool. Development (Cambridge, England) 75 26116661
2005 Expression of mouse dchs1, fjx1, and fat-j suggests conservation of the planar cell polarity pathway identified in Drosophila. Developmental dynamics : an official publication of the American Association of Anatomists 74 16059920
2006 Comparative integromics on FAT1, FAT2, FAT3 and FAT4. International journal of molecular medicine 70 16865240
2015 FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/β-catenin signalling. British journal of cancer 66 26633557
2015 Fat4/Dchs1 signaling between stromal and cap mesenchyme cells influences nephrogenesis and ureteric bud branching. Development (Cambridge, England) 63 26116666
2014 Regulation of neuronal migration by Dchs1-Fat4 planar cell polarity. Current biology : CB 63 24998526
2015 Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development. Development (Cambridge, England) 56 26209645
2020 Hedgehog-Activated Fat4 and PCP Pathways Mediate Mesenchymal Cell Clustering and Villus Formation in Gut Development. Developmental cell 52 32155439
2020 Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. The Journal of clinical investigation 50 32182215
2016 Dchs1-Fat4 regulation of polarized cell behaviours during skeletal morphogenesis. Nature communications 46 27145737
2019 miR-107 regulates growth and metastasis of gastric cancer cells via activation of the PI3K-AKT signaling pathway by down-regulating FAT4. Cancer medicine 42 31297980
2023 FAT4 overexpression promotes antitumor immunity by regulating the β-catenin/STT3/PD-L1 axis in cervical cancer. Journal of experimental & clinical cancer research : CR 41 37658376
2016 Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells. Cancer biology & therapy 36 26575609
2021 The novel FAT4 activator jujuboside A suppresses NSCLC tumorigenesis by activating HIPPO signaling and inhibiting YAP nuclear translocation. Pharmacological research 34 34116210
2011 Identification of fat4 and tsc22d1 as novel candidate genes for spontaneous pulmonary adenomas. Cancer research 34 21764761
2017 Dachsous1-Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 33 28705793
2019 FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling. Developmental cell 32 30853441
2018 Down-regulated long non-coding RNA RNAZFHX4-AS1 suppresses invasion and migration of breast cancer cells via FAT4-dependent Hippo signaling pathway. Cancer gene therapy 31 30546116
2019 Dchs1-Fat4 regulation of osteogenic differentiation in mouse. Development (Cambridge, England) 30 31358536
2016 Epigenetic inactivation of FAT4 contributes to gastric field cancerization. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 29 26792292
2016 Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae. Development (Cambridge, England) 28 27381226
2016 FAT4 functions as a tumor suppressor in triple-negative breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 26 27896700
2020 FAT4 silencing promotes epithelial-to-mesenchymal transition and invasion via regulation of YAP and β-catenin activity in ovarian cancer. BMC cancer 23 32366234
2016 FAT4 hypermethylation and grade dependent downregulation in gastric adenocarcinoma. Journal of cell communication and signaling 23 27696226
2017 A synthetic planar cell polarity system reveals localized feedback on Fat4-Ds1 complexes. eLife 22 28826487
2018 Aberrant methylation of FAT4 and SOX11 in peripheral blood leukocytes and their association with gastric cancer risk. Journal of Cancer 21 30026822
2019 FAT4-USP51 complex regulates the proliferation and invasion of endometrial cancer via Hippo pathway. American journal of translational research 20 31217854
2023 Structure of the planar cell polarity cadherins Fat4 and Dachsous1. Nature communications 17 36797229
2021 FAT4 identified as a potential modifier of orofacial cleft laterality. Genetic epidemiology 16 34130359
2020 MiR-106b-5p regulates the migration and invasion of colorectal cancer cells by targeting FAT4. Bioscience reports 15 33063118
2019 Targeted genomic profiling identifies frequent deleterious mutations in FAT4 and TP53 genes in HBV-associated hepatocellular carcinoma. BMC cancer 15 31395065
2022 A pan-cancer analysis of FAT atypical cadherin 4 (FAT4) in human tumors. Frontiers in public health 13 36051999
2022 FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228/Cer cells. Medical oncology (Northwood, London, England) 13 36576661
2023 FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways. Hepatology communications 11 38055646
2022 Increased expression of FAT4 suppress metastasis of lung adenocarcinoma through regulating MAPK pathway and associated with immune cells infiltration. Cancer medicine 11 35770846
2013 Nonsynonymous polymorphisms in FAT4 gene are associated with the risk of esophageal cancer in an Eastern Chinese population. International journal of cancer 9 23319386
2025 UBE4B promotes gastric cancer proliferation and metastasis by mediating FAT4 ubiquitination and degradation. Cell death & disease 6 40701960
2017 Whole-Exome Sequencing Reveals Mutations in a Clinically Unrecognizable Patient with Syndromic CAKUT: A Case Report. Molecular syndromology 6 28878612
2020 Up-regulation of FAT4 enhances the chemosensitivity of colorectal cancer cells treated by 5-FU. Translational cancer research 5 35117185
2025 Fat4 intracellular domain controls internalization of Fat4/Dchs1 planar polarity membrane complexes. Biophysical journal 3 39955614
2024 LATS2 and FAT4 as key candidate genes of hippo pathway associated with the risk and progression of breast cancer: an in-silico approach. Scientific reports 3 39572650
2024 IL-32 aggravates metabolic disturbance in human nucleus pulposus cells by activating FAT4-mediated Hippo/YAP signaling. International immunopharmacology 2 39178518
2026 RETRACTION: miR-107 Regulates Growth and Metastasis of Gastric Cancer Cells via Activation of the PI3K-AKT Signaling Pathway by Down-Regulating FAT4. Cancer medicine 0 41766484
2026 FAT4 loss promotes tumor growth and ferroptosis resistance in hepatocellular carcinoma via PI3K/AKT pathway activation. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 0 41832339
2026 Decreased Expression of FAT4 Promotes Multiple Myeloma Proliferation and Migration by Targeting the Hippo/YAP Pathway. Cancer science 0 42023818
2026 FAT4 restrains epithelial-mesenchymal transition and metastasis in cervical cancer and shapes the tumor immune microenvironment. Journal of translational medicine 0 42050622
2026 Research on the role and mechanism of FAT4 in the development and progression of tumor and non-tumor diseases. Discover oncology 0 42060002
2026 Bakuchiol Ameliorates Glucocorticoid-Induced Osteoporosis by Enhancing Osteoblast Differentiation via Targeting FAT4 to Activate YAP1. Phytotherapy research : PTR 0 42157729
2019 Kidneys Prefer a High Fat4 Diet. Developmental cell 0 30913403

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