Affinage

FAT4

Protocadherin Fat 4 · UniProt Q6V0I7

Length
4981 aa
Mass
542.7 kDa
Annotated
2026-04-28
53 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAT4 is a large atypical cadherin that functions as a core component of the non-canonical planar cell polarity (PCP) pathway, regulating oriented cell division, collective cell migration, and tissue morphogenesis across multiple organ systems including kidney, brain, heart, skeleton, gut, and lymphatic vasculature. FAT4 forms a high-affinity heterophilic trans-complex with its ligand DCHS1 through extracellular cadherin domains 1–4, and these boundary complexes are stabilized by a localized feedback mechanism controlled by the FAT4 intracellular domain via trans-endocytosis and actin polymerization (PMID:36797229, PMID:28826487, PMID:39955614). FAT4 modulates Hippo signaling non-canonically by sequestering Amotl1 and YAP in the cytoplasm independently of canonical Hippo kinases, directly interacts with the RET receptor to restrict RET-GFRA1-GDNF complex assembly during kidney development, and suppresses Wnt/β-catenin signaling by binding β-catenin and promoting its destruction-complex-mediated degradation (PMID:28239148, PMID:42023818, PMID:30853441, PMID:37658376). FAT4 protein levels are regulated by UBE4B-mediated ubiquitination and proteasomal degradation and stabilized by the deubiquitinase USP51 (PMID:40701960, PMID:31217854).

Mechanistic history

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

    Establishing that mammalian Fat4 functions in planar cell polarity answered whether Drosophila Fat-PCP signaling is conserved in vertebrates and identified Fat4 as essential for oriented cell division during kidney tubule elongation.

    Evidence Fat4 knockout mice with genetic epistasis against Vangl2 and Fjx1

    PMID:18604206

    Open questions at the time
    • Direct binding partner (Dachsous orthologue) not yet identified in mammals
    • Mechanism by which Fat4 controls cell orientation unknown
    • Relationship to Hippo pathway not tested
  2. 2011 High

    Demonstrating that Dchs1 and Fat4 function as a ligand–receptor pair across multiple organs established the core signaling module for vertebrate Fat-PCP and resolved the identity of the mammalian Dachsous orthologue partnering Fat4.

    Evidence Phenotypic comparison of Dchs1 and Fat4 knockout mice across ear, kidney, skeleton, intestine, heart, and lung

    PMID:21303848

    Open questions at the time
    • Direct physical interaction not yet demonstrated biochemically
    • Downstream intracellular effectors uncharacterized
    • Whether Fat4-Dchs1 signals through Hippo pathway untested
  3. 2013 High

    Placing Fat4-Dchs1 upstream of YAP in cortical neurogenesis linked Fat-PCP signaling to the Hippo pathway for the first time in mammals, revealing that Fat4 loss increases neural progenitors via YAP activation.

    Evidence Mouse neuroepithelium knockdown with genetic epistasis using concurrent Yap knockdown

    PMID:24056717

    Open questions at the time
    • Whether Fat4 acts on YAP through canonical Hippo kinases or via an alternative mechanism unknown
    • Direct protein–protein interactions between Fat4 and Hippo components not shown
  4. 2014 High

    Demonstrating that Fat4-Dchs1 controls tangential migration of facial branchiomotor neurons along one axis while Frizzled-PCP controls the orthogonal axis established that Fat-PCP and core-PCP operate as independent, axis-specific polarity systems.

    Evidence Conditional knockout mice with mosaic inactivation and cell polarity analysis

    PMID:24998526

    Open questions at the time
    • Molecular mechanism distinguishing Fat-PCP from Frizzled-PCP axis specification not resolved
    • Whether Fat4-Dchs1 gradients are instructive or permissive for migration unclear
  5. 2015 High

    Tissue-specific dissection of Fat4 in kidney development revealed that Fat4 acts non-autonomously from the stroma to regulate nephron progenitor self-renewal and, critically, that this function is YAP-independent, demonstrating context-dependent Hippo pathway engagement.

    Evidence Tissue-specific conditional knockouts, Fat4/Yap and Fat4/Six2 double-mutant epistasis

    PMID:26116661 PMID:26116666

    Open questions at the time
    • Alternative downstream effector in stroma not identified
    • How stromal Fat4 communicates non-autonomously to cap mesenchyme at the molecular level unknown
  6. 2015 High

    Identifying that Fat1 and Fat4 form cis-heterodimers and recruit distinct sets of actin-regulating proteins revealed a mechanism for integrating diverse intracellular signals at apical junctions during neural tube closure.

    Evidence Co-immunoprecipitation for cis-heterodimer, proteomics of interactors, mouse knockout genetics

    PMID:26209645

    Open questions at the time
    • Stoichiometry and structural basis of Fat1-Fat4 heterodimer not resolved
    • Whether cis-heterodimer formation is constitutive or regulated unknown
  7. 2016 High

    Showing that Fat4-Dchs1 establishes polarized cell behavior intrinsically within mesenchyme (sternum) and independently of Yap/Taz (vertebral column) demonstrated that Fat4-PCP operates via Hippo-independent effectors in skeletal development.

    Evidence Fat4/Dchs1 knockout mice with cell orientation analysis; Fat4/Yap and Fat4/Taz double-mutant epistasis with Ctgf readout

    PMID:27145737 PMID:27381226

    Open questions at the time
    • Identity of Hippo-independent effectors in skeletal mesenchyme unknown
    • Whether Fat4 directly transduces mechanical signals in mesenchyme not tested
  8. 2017 High

    Identifying Amotl1 as the intermediary that Fat4 sequesters out of the nucleus to prevent YAP co-activation in cardiomyocytes resolved how Fat4 modulates Hippo signaling non-canonically without affecting Hippo kinase activity.

    Evidence Fat4 knockout mouse hearts, subcellular fractionation of Amotl1/Yap1, Hippo kinase activity assays

    PMID:28239148

    Open questions at the time
    • Whether Amotl1 sequestration mechanism operates in tissues beyond the heart untested
    • Direct binding between Fat4 intracellular domain and Amotl1 not demonstrated
  9. 2017 High

    Reconstitution of Fat4-Dchs1 complex dynamics showed that boundary complexes exhibit dramatically reduced mobility and threshold-like accumulation, establishing a biophysical model for how Fat4-Dchs1 generates polarized signaling at cell interfaces.

    Evidence Synthetic biology platform with human Fat4/Ds1, quantitative live imaging, FRAP

    PMID:28826487

    Open questions at the time
    • Molecular identity of the feedback mechanism stabilizing boundary complexes not determined
    • Role of intracellular domain in complex dynamics not yet dissected
  10. 2019 High

    Demonstrating that FAT4 directly binds RET receptor and restricts RET-GFRA1-GDNF complex assembly revealed a juxtacrine signaling function for FAT4 distinct from its Hippo and PCP roles, explaining kidney phenotypes via titration of growth factor signaling.

    Evidence Co-immunoprecipitation, Gdnf heterozygous rescue of Fat4−/− kidney, RET signaling assays

    PMID:30853441

    Open questions at the time
    • Which specific cadherin repeats mediate RET interaction not mapped
    • Whether Fat4-RET interaction occurs in non-renal tissues unknown
  11. 2019 Medium

    Identifying that USP51 deubiquitinates and stabilizes FAT4 protein established the first post-translational regulatory axis controlling FAT4 abundance.

    Evidence Co-immunoprecipitation of USP51-FAT4, knockdown/overexpression affecting FAT4 levels

    PMID:31217854

    Open questions at the time
    • Ubiquitination sites on FAT4 not mapped
    • E3 ligase counterpart not identified in this study
    • Single-lab finding without independent replication
  12. 2020 High

    Establishing that Fat4 is a GATA2 target gene required cell-autonomously for flow-induced polarity in lymphatic endothelium placed Fat4 within the transcriptional hierarchy controlling lymphatic valve morphogenesis.

    Evidence Lymphatic endothelial cell-specific conditional knockout, flow polarity assays, GATA2 ChIP/reporter

    PMID:32182215

    Open questions at the time
    • Mechanosensory mechanism linking flow to Fat4-dependent polarity not identified
    • Whether Dchs1 is the relevant ligand in lymphatic valves not confirmed
  13. 2020 High

    Demonstrating that Hedgehog/GLI2 transcriptionally activates Fat4 and Dchs1 for mesenchymal cell clustering in gut villus formation connected Fat4-PCP to upstream morphogen regulation and showed it operates in parallel with core Vangl2-PCP.

    Evidence Fat4/Dchs1 knockout mice, GLI2 ChIP, genetic interaction with Vangl2, live light-sheet imaging

    PMID:32155439

    Open questions at the time
    • Whether Hedgehog regulation of Fat4 is conserved outside gut development unknown
    • Intracellular effectors mediating Fat4-driven mesenchymal clustering not identified
  14. 2023 High

    Solving the co-crystal structure of Fat4-Dchs1 EC1–4 revealed an extensive salt-bridge network underlying one of the highest-affinity cadherin interactions known and predicted that extracellular phosphorylation directly modulates binding affinity, providing a structural basis for graded signaling.

    Evidence X-ray crystallography, biophysical affinity measurements, structural modeling

    PMID:36797229

    Open questions at the time
    • Functional validation of phosphorylation-dependent affinity modulation in vivo not performed
    • Whether the kinase responsible for extracellular phosphorylation (Four-jointed orthologue) acts on mammalian Fat4-Dchs1 not confirmed
  15. 2023 Medium

    Showing that FAT4 directly binds β-catenin and promotes its destruction-complex-mediated degradation mechanistically explained how FAT4 suppresses Wnt/β-catenin signaling, with downstream consequences for PD-L1 transcription and glycosylation.

    Evidence Co-immunoprecipitation of FAT4–β-catenin, functional assays in vitro and in vivo, xenograft models

    PMID:37658376

    Open questions at the time
    • Domain on FAT4 mediating β-catenin binding not mapped
    • Single-lab finding; independent validation of FAT4–β-catenin direct interaction needed
    • Whether this mechanism operates in normal development or only cancer contexts unknown
  16. 2025 High

    Demonstrating that the Fat4 intracellular domain controls trans-endocytosis of Dchs1 and actin-dependent boundary accumulation resolved how Fat4-Dchs1 complex dynamics are regulated at cell interfaces, completing the biophysical model initiated in 2017.

    Evidence ICD deletion mutants, quantitative live imaging, FRAP, actin polymerization inhibition

    PMID:39955614

    Open questions at the time
    • Specific ICD motifs and binding partners mediating trans-endocytosis not identified
    • Whether trans-endocytosis is required for downstream PCP signaling not tested in vivo
  17. 2025 Medium

    Identifying UBE4B as the E4 ubiquitin ligase that ubiquitinates FAT4 for proteasomal degradation completed the ubiquitin-mediated regulatory circuit (with USP51 as the opposing deubiquitinase) governing FAT4 protein turnover.

    Evidence TMT proteomics, co-immunoprecipitation, ubiquitination assays, xenograft model

    PMID:40701960

    Open questions at the time
    • Specific ubiquitination sites on FAT4 not mapped
    • Whether UBE4B and USP51 compete for the same FAT4 pool not tested
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of intracellular effectors mediating Fat4's Hippo-independent, YAP-independent functions in kidney and skeleton; the structural basis for Fat4 cis-heterodimer formation with Fat1; whether extracellular phosphorylation modulates Fat4-Dchs1 affinity in vivo; and the specific ICD motifs that recruit endocytic and actin-regulatory machinery to drive trans-endocytosis.
  • No in vivo validation of phosphorylation-dependent affinity tuning
  • Hippo-independent downstream effectors remain molecularly unidentified
  • Structural basis of Fat1-Fat4 cis-heterodimer unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 7 GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-1266738 Developmental Biology 9 R-HSA-1500931 Cell-Cell communication 8 R-HSA-162582 Signal Transduction 7
Partners
AMOTL1CTNNB1DCHS1FAT1RETUBE4BUSP51YAP1
Complex memberships
Fat1-Fat4 cis-heterodimerFat4-Dchs1 trans-heterodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Fat4 is required for planar cell polarity (PCP) signaling and oriented cell divisions during kidney tubule elongation; loss of Fat4 disrupts PCP and leads to cystic kidney disease. Fat4 genetically interacts with PCP genes Vangl2 and Fjx1, and Fat4 represses Fjx1 expression, indicating conservation of Fat signaling. Gene-targeted knockout mouse, genetic epistasis (Fat4;Vangl2, Fat4;Fjx1 double mutants), oriented cell division analysis Nature genetics High 18604206
2011 Dchs1 and Fat4 function as a ligand-receptor pair during murine development. Mutation of either gene increases protein staining for the other, and single/double mutants display similar phenotypes across multiple organs (ear, kidney, skeleton, intestine, heart, lung), indicating they act in the same pathway. Gene-targeted knockout mouse (Dchs1 mutant), phenotypic comparison with Fat4 mutants, immunostaining Development (Cambridge, England) High 21303848
2013 FAT4 and DCHS1 (receptor-ligand cadherin pair) regulate cerebral cortical neurogenesis; loss of either increases neural progenitor numbers and reduces differentiation. These effects were countered by concurrent knockdown of Yap, placing Dchs1 and Fat4 upstream of Yap in the Hippo signaling pathway during neurogenesis. Mouse embryonic neuroepithelium knockdown, genetic epistasis with Yap knockdown, cell counting assays Nature genetics High 24056717
2014 Fat4 and Dchs1 are expressed in complementary gradients and are required for collective tangential migration of facial branchiomotor (FBM) neurons and their planar cell polarity. Fat4 and Dchs1 act intrinsically within FBM neurons and extrinsically in the neuroepithelium. Fat-PCP and Frizzled-PCP regulate FBM migration along orthogonal axes. Conditional knockout mouse, mosaic inactivation, cell polarity analysis, genetic interaction studies Current biology : CB High 24998526
2015 FAT4 acts non-autonomously in the renal stroma to control nephron progenitor (cap mesenchyme) self-renewal. Loss of Yap from cap mesenchyme in Fat4-null mice does not rescue the expanded progenitor pool, demonstrating FAT4 regulates cap mesenchyme independently of YAP. Excess progenitors in Fat4 mutants depend on Six2 (genetic epistasis). Dchs1 and its paralogue Dchs2 function in the cap mesenchyme to restrict progenitor numbers. Tissue-specific conditional knockout, Fat4/Six2 double mutants, electron microscopy, gene expression analysis Development (Cambridge, England) High 26116661
2015 Dchs1 protein localizes in a polarized manner within cap mesenchyme cells, accumulating at the interface with stromal cells, indicating direct interaction with a stromal protein (Fat4). Dchs1 mutation reduces ureteric bud branching and impairs nephron morphogenesis and is required within cap mesenchyme cells. Antibody staining of genetic mosaics, conditional knockout, polarization analysis Development (Cambridge, England) High 26116666
2015 Fat1 and Fat4 interact genetically to regulate cranial neural tube closure, cortical precursor proliferation, and apical constriction. Proteomic analysis reveals Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins. In vitro data show Fat1 and Fat4 form cis-heterodimers, providing a mechanism for coordinating diverse interactors at apical junctions. Mouse knockout genetics, in utero electroporation knockdown, proteomic analysis, co-IP/pulldown for cis-heterodimer Development (Cambridge, England) High 26209645
2016 Dchs1-Fat4 PCP pathway controls cell orientation within the early skeletal condensation to define shape and dimensions of the mouse sternum, driving cell intercalation. This is the first demonstration that Fat4 and Dchs1 establish polarized cell behavior intrinsically within mesenchyme. Knockout mouse analysis, cell orientation measurements, live imaging of mesenchymal cell polarity Nature communications High 27145737
2016 Fat4-Dchs1 regulates vertebral development by controlling cell proliferation in the early sclerotome independently of Yap and Taz. Genetic analysis of Fat4;Yap and Fat4;Taz double mutants and expression of transcriptional target Ctgf indicates Fat4-Dchs1 signaling uses a Hippo-independent mechanism for vertebral proliferation. Fat4/Dchs1 knockout mice, Fat4;Yap and Fat4;Taz double mutants, Ctgf expression analysis Development (Cambridge, England) High 27381226
2017 In the mouse heart, Fat4 modulates Hippo signaling to restrict cardiomyocyte growth and proliferation. Fat4 is not required for canonical Hippo kinase activation but sequesters Amotl1 out of the nucleus. Nuclear translocation of Amotl1 accompanies Yap1 to promote cardiomyocyte proliferation, identifying Amotl1 as a mammalian-specific intermediate for non-canonical Hippo signaling downstream of Fat4. Fat4 knockout mouse, cardiomyocyte size/proliferation assays, subcellular fractionation of Amotl1/Yap1, Hippo kinase activity assays Nature communications High 28239148
2017 Fat4-Ds1 (Dchs1) complexes accumulate at cell boundaries in a threshold-like manner and exhibit dramatically slower dynamics than unbound Fat4 and Ds1, indicating 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 with mammalian cells expressing human Fat4 and Ds1, quantitative live imaging, FRAP eLife High 28826487
2017 Fat4 and Dachsous1 are specifically required for lymphatic valve morphogenesis. Valve endothelial cells are disoriented and fail to form proper valve leaflets in Fat4 and Dachsous1 knockout mice. Dachsous1 is polarized to membrane protrusions and cellular junctions of valve endothelial cells. Fat4 and Dachsous1 knockout mouse, Lifeact-GFP live imaging, immunostaining of polarized Dchs1 localization Arteriosclerosis, thrombosis, and vascular biology High 28705793
2019 FAT4 directly interacts with RET (tyrosine kinase receptor) through extracellular cadherin repeats. FAT4 expression perturbs assembly of the RET-GFRA1-GDNF complex, reducing RET signaling. Removal of one copy of Gdnf rescues Fat4−/− kidney development, supporting that FAT4 fine-tunes RET signaling via a juxtacrine mechanism. Co-immunoprecipitation, conditional knockout analysis, Gdnf heterozygous rescue genetics, RET signaling assays Developmental cell High 30853441
2019 Dchs1-Fat4 signaling is essential for osteoblast differentiation. Loss of Dchs1-Fat4 signaling leads to increased Yap-Tead activity and increased osteoprogenitor proliferation. Yap and Taz differentially regulate Runx2 transcriptional activity; Yap-Runx2 and Taz-Runx2 complex activities are altered in Dchs1/Fat4 mutant osteoblasts. Dchs1/Fat4 knockout mice, osteoblast differentiation assays, co-immunoprecipitation of Yap/Taz-Runx2 complexes, luciferase reporter assays Development (Cambridge, England) High 31358536
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 identified as a target gene of GATA2, a key transcriptional regulator of lymphatic vascular development. Conditional knockout (lymphatic endothelial cell-specific), flow-induced polarity assays, ChIP/reporter assays for GATA2 regulation The Journal of clinical investigation High 32182215
2020 Hedgehog signaling transcriptionally activates Fat4 and Dchs1 (via GLI2). Fat4 and Dchs1 are required for mesenchymal cell clustering and villus formation in gut development. The Fat4-Dchs1 axis acts in parallel to the core-Vangl2 PCP axis to control mesenchymal cell clustering and WNT5A-guided oriented cell migration. Fat4 and Dchs1 knockout mice, GLI2 ChIP/transcriptomics, genetic interaction with Vangl2, live light-sheet fluorescence microscopy of PDGFRα+ cells Developmental cell High 32155439
2023 The co-crystal structure of human Fat4 and Dachsous1 (Dchs1) reveals that their binding domains form an extended interface along extracellular cadherin (EC) domains 1-4 of each protein. Fat4-Dchs1 affinity is among the highest reported for cadherin superfamily members, attributed to an extensive salt bridge network. Extracellular phosphorylation modifications are predicted to directly modulate Fat-Dachsous binding. X-ray crystallography (co-crystal structure), biophysical affinity measurements, structural modeling of phosphorylation effects Nature communications High 36797229
2016 Fat4 suppression in gastric cancer cells leads to increased phosphorylated Yap and nuclear accumulation of Yap, promoting proliferation and migration. Re-expression of full-length Fat4 decreases phosphorylated Yap and inhibits cell cycle progression. Fat4 reduction also leads to cytoplasmic accumulation of β-catenin. shRNA knockdown, Fat4 overexpression rescue, western blotting, nuclear fractionation Cancer biology & therapy Medium 26575609
2019 FAT4 regulates EMT and autophagy in colorectal cancer cells partially via the PI3K-AKT signaling pathway, specifically through PI3K/AKT/mTOR and PI3K/AKT/GSK-3β signaling axes. Transwell invasion assays, MTT assays, western blotting, tumor xenograft model Journal of experimental & clinical cancer research : CR Medium 30832706
2015 FAT4 functions as a tumor suppressor in gastric cancer by modulating Wnt/β-catenin signaling; knockdown of FAT4 activates Wnt/β-catenin signaling and induces EMT. shRNA knockdown, western blotting for β-catenin pathway components, xenograft model British journal of cancer Medium 26633557
2019 FAT4 interacts with the deubiquitinating enzyme USP51; USP51 directly binds FAT4 and controls its protein level. Ablating USP51 decreases FAT4 protein level while overexpression of USP51 increases FAT4 protein level. This interaction is essential for FAT4's tumor suppressor function in endometrial cancer. Co-immunoprecipitation, shRNA knockdown, overexpression, Hippo pathway readouts American journal of translational research Medium 31217854
2023 FAT4 binds to β-catenin and antagonizes its nuclear localization, promotes phosphorylation and degradation of β-catenin by the destruction complex (AXIN1, APC, GSK3β, CK1). FAT4 overexpression decreases PD-L1 mRNA expression transcriptionally and causes aberrant PD-L1 glycosylation via STT3A, leading to PD-L1 degradation — all in a β-catenin-dependent manner. Co-immunoprecipitation (FAT4-β-catenin), functional/mechanistic experiments in vivo and in vitro, immunofluorescence, xenograft models Journal of experimental & clinical cancer research : CR Medium 37658376
2025 UBE4B (ubiquitin factor E4B) directly binds to FAT4 and mediates its ubiquitination and proteasomal degradation, thereby inhibiting FAT4-dependent autophagy and promoting gastric cancer progression. Co-immunoprecipitation, quantitative TMT proteomics, ubiquitination assay, western blotting, xenograft model Cell death & disease Medium 40701960
2024 IL-32 interacts with FAT4 and MST1/2 proteins (identified by immunoprecipitation and mass spectrometry), promoting MST1/2 phosphorylation and activating the Hippo/YAP signaling pathway, causing matrix metabolism disorder in nucleus pulposus cells. Immunoprecipitation and mass spectrometry, western blotting, lentiviral knockdown, in vivo rat model International immunopharmacology Medium 39178518
2025 The intracellular domain (ICD) of Fat4 controls trans-endocytosis of Dchs1 into Fat4 cells and boundary accumulation of Fat4/Dchs1 complexes. Removing the Fat4 ICD reduces both trans-endocytosis and boundary accumulation but does not affect complex diffusion at the boundary. Actin polymerization is required for boundary accumulation of Fat4/Dchs1 complexes. Quantitative live imaging, ICD deletion mutants, actin polymerization inhibition, FRAP Biophysical journal High 39955614
2026 FAT4 directly interacts with YAP via co-immunoprecipitation. This interaction retains YAP in the cytoplasm to block its nuclear translocation, independently of canonical Hippo phosphorylation cascade, suppressing proliferation and migration in multiple myeloma cells. Co-immunoprecipitation, FAT4 knockdown in vitro and in vivo (zebrafish and mouse), nuclear/cytoplasmic fractionation Cancer science Medium 42023818

Source papers

Stage 0 corpus · 53 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 414 18604206
2013 Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nature genetics 213 24056717
2011 Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. Development (Cambridge, England) 167 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 154 30832706
2014 Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Human genetics 111 24913602
2009 Identification of Fat4 as a candidate tumor suppressor gene in breast cancers. International journal of cancer 90 19048595
2017 Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth. Nature communications 81 28239148
2015 Stromal Fat4 acts non-autonomously with Dchs1/2 to restrict the nephron progenitor pool. Development (Cambridge, England) 74 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 65 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 61 24998526
2015 Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development. Development (Cambridge, England) 55 26209645
2020 Hedgehog-Activated Fat4 and PCP Pathways Mediate Mesenchymal Cell Clustering and Villus Formation in Gut Development. Developmental cell 50 32155439
2020 Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. The Journal of clinical investigation 48 32182215
2016 Dchs1-Fat4 regulation of polarized cell behaviours during skeletal morphogenesis. Nature communications 43 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 39 37658376
2016 Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells. Cancer biology & therapy 34 26575609
2011 Identification of fat4 and tsc22d1 as novel candidate genes for spontaneous pulmonary adenomas. Cancer research 34 21764761
2021 The novel FAT4 activator jujuboside A suppresses NSCLC tumorigenesis by activating HIPPO signaling and inhibiting YAP nuclear translocation. Pharmacological research 33 34116210
2017 Dachsous1-Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 32 28705793
2019 FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling. Developmental cell 31 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
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
2019 Dchs1-Fat4 regulation of osteogenic differentiation in mouse. Development (Cambridge, England) 28 31358536
2016 Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae. Development (Cambridge, England) 26 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
2017 A synthetic planar cell polarity system reveals localized feedback on Fat4-Ds1 complexes. eLife 22 28826487
2016 FAT4 hypermethylation and grade dependent downregulation in gastric adenocarcinoma. Journal of cell communication and signaling 22 27696226
2020 FAT4 silencing promotes epithelial-to-mesenchymal transition and invasion via regulation of YAP and β-catenin activity in ovarian cancer. BMC cancer 21 32366234
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 18 31217854
2023 Structure of the planar cell polarity cadherins Fat4 and Dachsous1. Nature communications 15 36797229
2021 FAT4 identified as a potential modifier of orofacial cleft laterality. Genetic epidemiology 15 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 13 31395065
2022 FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228/Cer cells. Medical oncology (Northwood, London, England) 12 36576661
2022 A pan-cancer analysis of FAT atypical cadherin 4 (FAT4) in human tumors. Frontiers in public health 11 36051999
2023 FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways. Hepatology communications 10 38055646
2022 Increased expression of FAT4 suppress metastasis of lung adenocarcinoma through regulating MAPK pathway and associated with immune cells infiltration. Cancer medicine 9 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
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 4 35117185
2025 UBE4B promotes gastric cancer proliferation and metastasis by mediating FAT4 ubiquitination and degradation. Cell death & disease 3 40701960
2025 Fat4 intracellular domain controls internalization of Fat4/Dchs1 planar polarity membrane complexes. Biophysical journal 2 39955614
2024 IL-32 aggravates metabolic disturbance in human nucleus pulposus cells by activating FAT4-mediated Hippo/YAP signaling. International immunopharmacology 2 39178518
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 2 39572650
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
2019 Kidneys Prefer a High Fat4 Diet. Developmental cell 0 30913403