Affinage

FRAT1

Proto-oncogene FRAT1 · UniProt Q92837

Length
279 aa
Mass
29.1 kDa
Annotated
2026-06-09
33 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FRAT1 is a positive regulator of Wnt/beta-catenin signaling that acts as a substrate-selective inhibitor of GSK-3 (PMID:10481074, PMID:11696357). A FRAT1 peptide (residues 188-226, "FRATtide") binds GSK-3 and blocks its phosphorylation of Axin-dependent substrates such as beta-catenin and Tau while sparing priming-dependent substrates like glycogen synthase and eIF2B, defining the molecular basis of its selectivity (PMID:10481074, PMID:11696357). Within the Wnt pathway, FRAT1 binds both Dishevelled and GSK-3 and is recruited into a quaternary Dvl-Axin-GSK3-Frat1 complex; Wnt-1 stimulation disintegrates this complex and dissociates GSK-3 from Axin, allowing beta-catenin to accumulate (PMID:10428961, PMID:24829151). Recruitment is organized at the membrane: FRAT1 binds the cytoplasmic tail of the Wnt co-receptor LRP5 and is drawn to the plasma membrane upon Wnt3a stimulation (PMID:15699046), and the Dvl-Frat1 interaction is licensed by CKI-epsilon-mediated phosphorylation of Dvl (PMID:12556519). By preventing GSK-3 from associating with the Axin1-APC-CK1 destruction complex, FRAT1 reduces beta-catenin phosphorylation at Ser33/37/Thr41 and drives its nuclear accumulation and TCF/LEF-dependent transcription (PMID:18498136, PMID:24829151). FRAT1 activity is constrained by PKA, which phosphorylates it at Ser188 to suppress its ability to activate beta-catenin-dependent transcription (PMID:16982607). Functionally, FRAT1 is an oncogenic progression gene cooperating with Pim1 and Myc in lymphomagenesis (PMID:9034327, PMID:10557087) and promotes tumor cell invasion, angiogenesis, and beta-catenin/TCF activity in multiple carcinomas, with FRAT1-FRAT2 heterodimerization required for maximal pro-invasive activity (PMID:18498136, PMID:36153370).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 Medium

    Established FRAT1 as an oncogenic progression gene before its biochemical function was known, motivating the search for its mechanism.

    Evidence Retroviral insertional mutagenesis and Frat1 overexpression in T-cell lymphoma models in vivo

    PMID:9034327

    Open questions at the time
    • No molecular mechanism linking Frat1 to tumor growth identified
    • Pathway context unknown at this stage
  2. 1999 High

    Placed FRAT1 within the Wnt pathway by showing it bridges Dvl and GSK3 and that Wnt signaling dissolves a Dvl-Axin-GSK3-Frat1 complex, explaining how FRAT1 relieves beta-catenin from GSK3.

    Evidence Co-immunoprecipitation, dominant-negative domains, and LEF-1 reporter assays in mammalian and Xenopus systems

    PMID:10428961

    Open questions at the time
    • Precise step at which GSK3 dissociates from Axin not resolved
    • Stoichiometry of the quaternary complex undefined
  3. 1999 High

    Defined the biochemical basis of FRAT1 action as substrate-selective GSK3 inhibition, distinguishing Axin-dependent from priming-dependent substrates.

    Evidence In vitro GSK3 kinase assays with the FRATtide peptide (residues 188-226) against beta-catenin, Axin, glycogen synthase, and eIF2B

    PMID:10481074

    Open questions at the time
    • Structural mechanism of selectivity not determined
    • Whether full-length FRAT1 behaves identically to the peptide not addressed here
  4. 1999 Medium

    Tested the in vivo requirement for Frat1, revealing functional redundancy with Frat3 that masks a loss-of-function phenotype.

    Evidence Frat1 knockout mouse with LacZ knock-in and Xenopus axis-induction assays

    PMID:10534617

    Open questions at the time
    • Redundancy not formally proven by compound knockout
    • Physiological Wnt context where Frat1 is non-redundant unidentified
  5. 1999 Medium

    Provided gain-of-function in vivo confirmation that Frat1 drives lymphoma progression and causes renal pathology.

    Evidence Frat1 transgenic mice, M-MuLV infection, and Frat1/Pim1 bitransgenic crosses

    PMID:10557087

    Open questions at the time
    • Mechanism connecting Frat1 to glomerulosclerosis not defined
    • Whether oncogenic effect requires beta-catenin not tested here
  6. 2001 Medium

    Confirmed substrate-selective GSK3 inhibition in a cellular context and extended FRAT1 function to neuroprotection via reduced Tau phosphorylation.

    Evidence Adenoviral FRAT1 overexpression in PC12 cells with substrate phosphorylation and survival assays

    PMID:11696357

    Open questions at the time
    • Direct neuronal relevance beyond PC12 cells not established
    • Mechanism of survival benefit not dissected
  7. 2003 High

    Identified CKI-epsilon as an upstream licensing kinase that phosphorylates Dvl to promote the Dvl-Frat1 interaction and downstream beta-catenin accumulation.

    Evidence Co-IP, CKI-epsilon RNAi epistasis, and Tcf-4 reporter assays in HeLa S3 cells

    PMID:12556519

    Open questions at the time
    • Phospho-residues on Dvl mediating Frat1 binding not mapped
    • Direct versus indirect effect on complex assembly not fully separated
  8. 2003 Medium

    Connected FRAT1-mediated GSK3 inhibition to reduced amyloid-beta production, implicating the pathway in Alzheimer-relevant processing.

    Evidence FRAT1 peptide expression in swAPP(751) cells with GSK3 kinase activity assays and Abeta ELISA

    PMID:14572648

    Open questions at the time
    • Mechanism linking GSK3 inhibition to Abeta reduction not detailed
    • In vivo relevance not tested
  9. 2005 Medium

    Localized FRAT1 recruitment to the Wnt receptor by demonstrating direct interaction with the LRP5 cytoplasmic domain and Wnt-induced membrane recruitment.

    Evidence Yeast two-hybrid, co-IP, membrane recruitment assays, and TCF-1 reporter

    PMID:15699046

    Open questions at the time
    • Whether LRP5 binding is required for GSK3 inhibition not isolated
    • Order of LRP5, Frat1, Axin assembly undefined
  10. 2006 High

    Revealed a regulatory input controlling FRAT1 itself, showing PKA phosphorylation at Ser188 dampens its beta-catenin-activating function.

    Evidence In vitro PKA kinase assay, phospho-site mass spectrometry, norepinephrine stimulation, and beta-catenin reporter assays

    PMID:16982607

    Open questions at the time
    • How Ser188 phosphorylation alters GSK3 binding not mechanistically resolved
    • Physiological contexts engaging this regulation not defined
  11. 2008 Medium

    Demonstrated that FRAT1 drives beta-catenin/TCF transcription and a c-Myc-dependent growth state in carcinoma, with GSK3beta as the antagonized node.

    Evidence FRAT1 gain/loss-of-function in ESCC cells with GSK3beta and dominant-negative TCF4 rescue

    PMID:18498136

    Open questions at the time
    • Direct biochemical block of GSK3 in these cells not shown
    • Generality across tumor types not tested here
  12. 2014 Medium

    Refined the mechanism to show FRAT1 prevents GSK3beta association with the Axin1-APC-CK1 destruction complex, blocking beta-catenin Ser33/37/Thr41 phosphorylation.

    Evidence Phospho-specific Western blotting, destruction-complex co-IP, and NDRG1/FRAT1 knockdown/overexpression in prostate and colon cancer cells

    PMID:24829151

    Open questions at the time
    • Mechanism by which NDRG1 upregulates FRAT1 not defined
    • Direct contact preventing GSK3-complex association not mapped
  13. 2017 Medium

    Identified post-transcriptional control of FRAT1 by miR-34a-3p, providing a route to modulate FRAT1 levels.

    Evidence Dual-luciferase 3'UTR reporter with binding-site mutation and Western blot in meningioma cells

    PMID:28340489

    Open questions at the time
    • Functional consequence on Wnt output in this context not shown
    • Other regulatory miRNAs not surveyed
  14. 2022 Medium

    Established FRAT1-FRAT2 heterodimerization as required for maximal pro-invasive activity and identified miR-3648 as a dual regulator.

    Evidence Co-IP, FRAT2 siRNA rescue, invasion assays, and miRNA target validation in gastric cancer cells

    PMID:36153370

    Open questions at the time
    • Structural basis of FRAT1-FRAT2 interaction unknown
    • Whether heterodimer alters GSK3 inhibition not tested
  15. 2022 Low

    Linked FRAT1 to tumor angiogenesis via VEGFA expression in glioblastoma cells.

    Evidence siRNA knockdown with RT-qPCR, Western blot, VEGFA ELISA, and tube formation assay in U251 cells

    PMID:35059733

    Open questions at the time
    • No epistasis establishing a direct Wnt/beta-catenin-to-VEGFA mechanism
    • Single cell line, knockdown-only evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural mechanism by which FRAT1 confers substrate selectivity on GSK3 and how Ser188 phosphorylation, LRP5 binding, and FRAT1-FRAT2 heterodimerization are integrated to control GSK3 release from Axin remain unresolved.
  • No structural model of the FRAT1-GSK3 complex in the timeline
  • Integration of regulatory inputs into a single quantitative model not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
AXIN1CSNK1EDVL1FRAT2GSK3BLRP5PRKACA
Complex memberships
Dvl-Axin-GSK3-Frat1 complexFRAT1-FRAT2 heterodimer

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Frat1 was identified as a proto-oncogene that collaborates with Pim1 and Myc in T-cell lymphoma progression; retroviral overexpression of Frat1 conferred selective in vivo growth advantage to tumor cells already expressing high Myc and Pim1, establishing Frat1 as a progression gene in lymphomagenesis. Retroviral insertional mutagenesis, proviral tagging, Frat1-IRES-lacZ retroviral overexpression in tumor cell lines transplanted in vivo The EMBO journal Medium 9034327
1999 Frat1 interacts with both Dvl and GSK3, and can be recruited into a quaternary Dvl-Axin-GSK3-Frat1 complex. Wnt-1 signaling promotes disintegration of this complex, leading to dissociation of GSK3 from Axin, suggesting Frat1 mediates GSK3 displacement from Axin downstream of Dvl. Co-immunoprecipitation, dominant-negative domain overexpression, LEF-1 luciferase reporter assay in mammalian cells The EMBO journal High 10428961
1999 A peptide from FRAT1 (FRATtide, residues 188-226) binds GSK3 and selectively blocks GSK3-catalysed phosphorylation of Axin and beta-catenin (Axin-dependent substrates) without suppressing GSK3 activity toward glycogen synthase or eIF2B (priming-dependent substrates), demonstrating substrate-selective inhibition of GSK3 by FRAT1. In vitro GSK3 kinase assay with FRATtide peptide against multiple substrates; direct binding assay FEBS letters High 10481074
1999 Frat1-deficient mice are normal and fertile, with no developmental phenotype; a second mouse gene Frat3 shares overlapping expression patterns with Frat1 and can also induce a secondary axis in Xenopus embryos, suggesting functional redundancy compensates for Frat1 loss. Frat1 knockout mouse (beta-galactosidase knock-in), LacZ reporter expression analysis, Xenopus axis induction assay Mechanisms of development Medium 10534617
1999 Transgenic overexpression of Frat1 in mice causes focal glomerulosclerosis and nephrotic syndrome, and markedly accelerates M-MuLV-induced lymphomagenesis in combination with Pim1, providing direct in vivo evidence that Frat1 promotes lymphoma progression. Frat1 transgenic mouse generation, M-MuLV infection, tumor incidence analysis, Frat1/Pim1 bitransgenic crosses Oncogene Medium 10557087
2001 Adenoviral overexpression of FRAT1 in PC12 cells confers neuroprotection and inhibits GSK-3 activity toward Tau and beta-catenin but does not affect GSK-3-mediated phosphorylation of glycogen synthase, confirming substrate-selective GSK-3 inhibition by FRAT1 in a cellular context. Adenoviral FRAT1 overexpression in PC12 cells, GSK-3 substrate phosphorylation assays (Tau, beta-catenin, glycogen synthase), cell survival assay FEBS letters Medium 11696357
2002 When transiently overexpressed in COS-1 cells, both hFRAT1 and hFRAT2 proteins localize to the cytosol and are concentrated in the nucleus. Transient transfection in COS-1 cells, subcellular fractionation/localization Gene Low 12095675
2003 CKI epsilon phosphorylates Dvl-1 and enhances the binding of Dvl-1 to Frat-1; depletion of CKI epsilon by RNAi inhibits Wnt-3a-induced Dvl phosphorylation, reduces Dvl-1/Frat-1 complex formation, and decreases Wnt-3a-induced beta-catenin accumulation, placing CKI epsilon upstream of the Dvl-Frat-1 interaction in Wnt signaling. Co-immunoprecipitation, RNAi knockdown of CKI epsilon in HeLa S3 cells, Tcf-4 luciferase reporter assay, beta-catenin accumulation assay The Journal of biological chemistry High 12556519
2003 Expression of a FRAT1 peptide in swAPP(751) cells increases phosphorylation of GSK3alpha (Ser21) and GSK3beta (Ser9), inhibits kinase activity of both isoforms, and significantly decreases production of total Abeta and Abeta(1-42). Cellular expression of FRAT1 peptide in swAPP(751) cells, GSK3 kinase activity assay, ELISA for Abeta FEBS letters Medium 14572648
2005 Frat1 interacts with the cytoplasmic domain of LRP5 (identified by yeast two-hybrid, confirmed by co-IP); Wnt3a or constitutively active LRP5 recruits Frat1 to the cell membrane; LRP5, Frat1, and Axin co-immunoprecipitate, suggesting a membrane-proximal complex in which Frat1 inhibits GSK3 to promote beta-catenin nuclear translocation. Yeast two-hybrid, co-immunoprecipitation, cell membrane recruitment assay, TCF-1 luciferase reporter The Journal of biological chemistry Medium 15699046
2006 FRAT1 is phosphorylated at Ser188 in vitro and in intact cells by protein kinase A (PKA); activation of endogenous beta-adrenergic receptors with norepinephrine stimulates Ser188 phosphorylation; PKA-mediated Ser188 phosphorylation inhibits FRAT1's ability to activate beta-catenin-dependent transcription. GSK-3 can phosphorylate FRAT1 at Ser188 in vitro but does not significantly phosphorylate endogenous FRAT1 in cells. In vitro PKA kinase assay, phospho-site mapping by mass spectrometry, norepinephrine stimulation in intact cells, beta-catenin-dependent transcription reporter assay, GSK-3 in vitro kinase assay The Journal of biological chemistry High 16982607
2008 FRAT1 overexpression in esophageal squamous cell carcinoma cells induces nuclear accumulation of beta-catenin and promotes beta-catenin/TCF transcriptional activity; these effects are reversed by co-expression of GSK3beta or dominant-negative TCF4; continued c-Myc expression is required for maintenance of the FRAT1-driven growth state. FRAT1 overexpression/RNAi in ESCC cells, beta-catenin localization by immunofluorescence, TCF reporter assay, co-expression rescue experiments International journal of cancer Medium 18498136
2014 NDRG1 upregulates FRAT1 expression, which prevents association of GSK3beta with the Axin1-APC-CK1 destruction complex, thereby inhibiting beta-catenin phosphorylation at Ser33/37 and Thr41 and increasing non-phosphorylated beta-catenin at the plasma membrane in prostate and colon cancer cells. Western blotting for phospho-beta-catenin, co-immunoprecipitation of destruction complex components, siRNA knockdown/overexpression of NDRG1 and FRAT1 Journal of cell science Medium 24829151
2017 FRAT1 is a direct target of miR-34a-3p; co-expression of miR-34a-3p with a reporter construct containing the FRAT1 3'UTR reduces luciferase activity, and disruption of the miR-34a-3p binding site in the FRAT1 3'UTR abolishes this regulation. In meningioma cells, miR-34a-3p overexpression decreases FRAT1 protein levels. Dual luciferase reporter assay with 3'UTR constructs and mutant binding sites, Western blotting after miR-34a-3p overexpression/inhibition Aging Medium 28340489
2022 FRAT1 and FRAT2 physically interact with each other; siRNA-mediated knockdown of FRAT2 in FRAT1-overexpressing gastric cancer cells reverses FRAT1-driven invasion, indicating the FRAT1-FRAT2 complex is required for maximal pro-invasive activity. miR-3648 directly targets FRAT1 and FRAT2 to inactivate Wnt/beta-catenin signaling. Co-immunoprecipitation of FRAT1-FRAT2, siRNA knockdown, invasion assays, dual-luciferase miRNA target validation Oncogene Medium 36153370
2022 siRNA knockdown of FRAT1 in glioblastoma U251 cells reduces mRNA and protein levels of VEGFA and decreases secreted VEGFA concentration, suppressing tube formation in an angiogenesis assay, linking FRAT1 activity through Wnt/beta-catenin signaling to VEGFA-mediated angiogenesis. siRNA knockdown, RT-qPCR, Western blotting, ELISA for secreted VEGFA, in vitro tube formation assay Molecular medicine reports Low 35059733

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. The EMBO journal 342 10428961
1999 A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin. FEBS letters 200 10481074
1997 Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas. The EMBO journal 123 9034327
2014 The metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of β-catenin through mechanisms involving FRAT1 and PAK4. Journal of cell science 98 24829151
2003 Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of beta-catenin. The Journal of biological chemistry 96 12556519
2001 GSK-3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and beta-catenin stabilisation without elevation of glycogen synthase activity. FEBS letters 82 11696357
2002 Molecular cloning and expression of proto-oncogene FRAT1 in human cancer. International journal of oncology 76 11894125
2001 FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer. International journal of oncology 76 11445844
2005 Interaction between LRP5 and Frat1 mediates the activation of the Wnt canonical pathway. The Journal of biological chemistry 62 15699046
2017 MiR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro and is directly targeting SMAD4, FRAT1 and BCL2. Aging 41 28340489
2008 FRAT1 overexpression leads to aberrant activation of beta-catenin/TCF pathway in esophageal squamous cell carcinoma. International journal of cancer 33 18498136
1999 In vivo analysis of Frat1 deficiency suggests compensatory activity of Frat3. Mechanisms of development 31 10534617
2019 LncRNA SNHG1 influences cell proliferation, migration, invasion, and apoptosis of non-small cell lung cancer cells via the miR-361-3p/FRAT1 axis. Thoracic cancer 30 31788970
1999 Overexpression of Frat1 in transgenic mice leads to glomerulosclerosis and nephrotic syndrome, and provides direct evidence for the involvement of Frat1 in lymphoma progression. Oncogene 26 10557087
2012 Expression of Frat1 correlates with expression of β-catenin and is associated with a poor clinical outcome in human SCC and AC. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 22528942
2002 Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2. Gene 25 12095675
2013 Knockdown of FRAT1 expression by RNA interference inhibits human glioblastoma cell growth, migration and invasion. PloS one 24 23613813
2009 FRAT1 expression and its correlation with pathologic grade, proliferation, and apoptosis in human astrocytomas. Medical oncology (Northwood, London, England) 24 20041315
2022 The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells. Oncogene 21 36153370
2011 Overexpression of Frat1 correlates with malignant phenotype and advanced stage in human non-small cell lung cancer. Virchows Archiv : an international journal of pathology 21 21818639
2015 The clinical significance of FRAT1 and ABCG2 expression in pancreatic ductal adenocarcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 19 26178481
2006 FRAT1, a substrate-specific regulator of glycogen synthase kinase-3 activity, is a cellular substrate of protein kinase A. The Journal of biological chemistry 15 16982607
2016 Knockdown of FRAT1 inhibits hypoxia-induced epithelial-to-mesenchymal transition via suppression of the Wnt/β-catenin pathway in hepatocellular carcinoma cells. Oncology reports 13 27666874
2020 FRAT1 Enhances the Proliferation and Tumorigenesis of CD133+Nestin+ Glioma Stem Cells In Vitro and In Vivo. Journal of Cancer 12 32201513
2003 FRAT1 peptide decreases Abeta production in swAPP(751) cells. FEBS letters 12 14572648
2021 LncRNA CCAT1 promotes prostate cancer cells proliferation, migration, and invasion through regulation of miR-490-3p/FRAT1 axis. Aging 10 34319909
2020 Swertiamarin suppresses proliferation, migration, and invasion of hepatocellular carcinoma cells <em>via</em> negative regulation of FRAT1. European journal of histochemistry : EJH 10 33131270
2014 The clinical pathological significance of FRAT1 and ROR2 expression in cartilage tumors. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 9 25387569
1992 Molecular cloning and sequencing of the attachment site and integrase gene of the temperate mycobacteriophage FRAT1. Nucleic acids research 9 1561099
2016 Silencing of FRAT1 by siRNA inhibits the proliferation of SGC7901 human gastric adenocarcinoma cells. Biomedical reports 7 26893843
2022 FRAT1 promotes the angiogenic properties of human glioblastoma cells via VEGFA. Molecular medicine reports 5 35059733
2016 FRAT1 expression regulates proliferation in colon cancer cells. Oncology letters 4 28101222
2022 Overexpression of FRAT1 protein is closely related to triple-negative breast cancer. Annals of surgical treatment and research 2 36017142

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