Affinage

FRAS1

Extracellular matrix organizing protein FRAS1 · UniProt Q86XX4

Length
4008 aa
Mass
443.2 kDa
Annotated
2026-06-09
42 papers in source corpus 18 papers cited in narrative 18 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

FRAS1 encodes a large extracellular matrix protein essential for epithelial-mesenchymal adhesion, whose loss causes Fraser syndrome in humans and the blebbed phenotype in mice (PMID:12766769). The protein localizes in a linear pattern to the basal surface of epithelia, specifically within the sublamina densa of basement membranes where it forms clustered depositions attached to anchoring fibrils (PMID:12766770, PMID:17576586). There it assembles a mutually stabilizing ternary complex with FREM1 and FREM2 (anchoring cords): loss of any single member depletes all three from the basement membrane zone, and FRAS1 is additionally required for the intracellular trafficking and export of FREM2 from epithelial cells (PMID:16880404, PMID:17596926, PMID:37047755). Correct delivery of FRAS1 to the basal cell surface depends on the cytoplasmic multi-PDZ scaffold GRIP1, which binds the FRAS1 C-terminal peptide through a PDZ1-PDZ2 supramodule in which only the PDZ1 groove engages the ligand and PDZ1 folding requires covalent linkage to PDZ2 (PMID:14730302, PMID:18155042). Through this adhesive function FRAS1 supports organogenesis across multiple systems—ureteric bud invasion in kidney development via GDNF/GDF11 (PMID:18787044), glomerular maturation (PMID:22730198), interdigital cell death and digit separation through BMP/Msx2 signaling (PMID:26813283), and pharyngeal pouch and craniofacial morphogenesis acting with integrin alpha-8 (ITGA8) (PMID:22782724, PMID:27265864). FRAS1 protein abundance is controlled by CRL4-DCAF13-mediated polyubiquitination and proteasomal degradation, and FRAS1 can activate FAK signaling to promote cancer cell migration and proliferation (PMID:39367995).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 High

    Established the molecular cause of Fraser syndrome and the murine blebbed phenotype, defining FRAS1 as an ECM-related protein required for epithelial integrity.

    Evidence Autozygosity mapping and mutation analysis in human patients plus identification of premature termination in bl/bl mice, with protein domain analysis

    PMID:12766769

    Open questions at the time
    • Did not resolve subcellular/ultrastructural localization
    • Did not identify molecular partners or trafficking machinery
  2. 2003 High

    Localized Fras1 protein to the basal epithelial surface and tied its loss directly to subepidermal blistering and renal agenesis, linking molecular site to phenotype.

    Evidence Immunolocalization in embryonic mouse tissues and knockout/bl-mutant phenotype analysis

    PMID:12766770

    Open questions at the time
    • Mechanism of basal targeting unknown
    • Whether Fras1 acts alone or in a complex not addressed
  3. 2004 High

    Identified GRIP1 as the cytoplasmic scaffold required to deliver Fras1 to the basal cell surface, explaining a genetically distinct route to Fraser-like phenotypes.

    Evidence Co-immunoprecipitation of GRIP1 with Fras1, genetic analysis of the eb mouse, and loss-of-function phenotyping

    PMID:14730302

    Open questions at the time
    • Structural basis of the interaction not defined
    • Trafficking step (export vs. surface retention) not pinpointed
  4. 2006 High

    Defined the Fras1/Frem1/Frem2 ternary complex and its reciprocal stabilization, establishing that the three proteins act as an interdependent unit in the basement membrane.

    Evidence Immunofluorescence across multiple Fraser-model mouse mutants and transfection/secretion assays demonstrating complex formation

    PMID:16880404 PMID:17240369

    Open questions at the time
    • Stoichiometry and binding interfaces of the complex not determined
    • Extracellular receptor/anchor on the mesenchymal side unknown
  5. 2007 High

    Resolved the atomic basis of FRAS1 recognition by GRIP1, showing PDZ1-PDZ2 act as a single supramodule with PDZ1 dependent on PDZ2 for folding and ligand binding.

    Evidence Crystal structure of GRIP1 PDZ12 in complex with the Fras1 C-terminal peptide plus domain folding analysis

    PMID:18155042

    Open questions at the time
    • Does not address how the complex transits to the cell surface
    • In vivo consequence of disrupting the specific interface not tested
  6. 2007 Medium

    Placed FRAS1 ultrastructurally in the sublamina densa attached to anchoring fibrils and near mesenchyme, providing a physical model for epithelial-mesenchymal linkage.

    Evidence Pre-embedding immunoelectron microscopy in multiple embryonic mouse epithelia

    PMID:17576586

    Open questions at the time
    • Single lab
    • Molecular identity of the mesenchymal anchoring partner not established
  7. 2007 Medium

    Showed FRAS1 is needed for intracellular export of FREM2 and that FREM3 anchors independently, separating Fras1-dependent from Fras1-independent basement membrane assembly.

    Evidence Immunofluorescence of Frem2 and Frem3 in Fras1-null versus wild-type embryonic skin

    PMID:17596926

    Open questions at the time
    • Trafficking mechanism by which Fras1 promotes Frem2 export unresolved
    • Single lab
  8. 2008 Medium

    Linked FRAS1 adhesive function to kidney organogenesis, showing ureteric bud invasion failure correlates with reduced GDNF/GDF11 and is rescued by these growth factors.

    Evidence bl/bl mouse and organ-culture rescue with GDNF/GDF11, plus expression and immunolocalization analysis

    PMID:18787044

    Open questions at the time
    • How adhesion defects feed into growth factor expression not mechanistically defined
    • Single lab
  9. 2012 Medium

    Demonstrated tissue-autonomous and locally required roles for fras1 in endoderm-driven pharyngeal morphogenesis and in glomerular maturation, broadening its organogenetic reach.

    Evidence Zebrafish mutant analysis with cell transplantation, and podocyte-specific conditional Fras1 deletion in mice

    PMID:22730198 PMID:22782724

    Open questions at the time
    • Downstream effectors in pharyngeal/glomerular contexts not fully resolved
    • Single labs
  10. 2016 Medium

    Connected FRAS1-dependent adhesion to developmental signaling, showing syndactyly arises from failed BMP/Msx2-driven interdigital cell death and that fras1 cooperates with itga8 in craniofacial morphogenesis within a defined time window.

    Evidence Fras1(rdf) mouse with BMP/Msx2 in situ analysis, and zebrafish fras1/itga8 double-mutant and revertible-allele genetics

    PMID:26813283 PMID:27265864

    Open questions at the time
    • Direct molecular bridge from adhesion to BMP signal transmission not established
    • ITGA8-FRAS1 physical interaction not demonstrated
  11. 2020 Medium

    Extended FRAS1 function beyond classical Fraser phenotypes to brain ECM organization and cognition, implicating it in perineuronal-net-type matrix integrity and behavior.

    Evidence Expression mapping, behavioral testing of Fras1-/- mice, and WFA immunolabeling of cortical/subcortical ECM

    PMID:32333816

    Open questions at the time
    • Molecular role of Fras1 in brain ECM not defined
    • Single lab
  12. 2024 Medium

    Identified post-translational control of FRAS1 by CRL4-DCAF13-mediated ubiquitination/degradation and a pro-tumorigenic FAK-activating output in cancer cells.

    Evidence DCAF13 CRISPR knockout, polyubiquitination and proteasomal degradation assays, and migration/proliferation assays with FAK Western blots

    PMID:25126166 PMID:39367995

    Open questions at the time
    • FAK activation mechanism by an ECM protein not detailed
    • Cancer cell-line context may not reflect canonical developmental function

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the FRAS1/FREM ternary complex physically bridges the sublamina densa to mesenchymal receptors, and how FRAS1 abundance and signaling are integrated to control adhesion versus migration, remain unresolved.
  • Mesenchymal receptor for the anchoring cords unidentified
  • No structural model of the full Fras1/Frem1/Frem2 complex
  • Mechanistic basis of FRAS1-driven FAK activation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0031012 extracellular matrix 4 GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-392499 Metabolism of proteins 1
Partners
DCAF13FREM1FREM2GRIP1ITGA8
Complex memberships
Fras1/Frem1/Frem2 ternary complex (Fraser complex / anchoring cords)

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 FRAS1 encodes a protein with N-terminal cysteine-rich repeat motifs related to an ECM blastocoelar protein found in sea urchin, and loss-of-function mutations in FRAS1/Fras1 cause Fraser syndrome in humans and the blebbed phenotype in mice, establishing its role in epithelial integrity via disrupted ECM function. Autozygosity mapping, mutation analysis (frameshift mutations in patients), identification of premature termination in bl/bl mice, protein domain analysis Nature genetics High 12766769
2003 Fras1 protein localizes specifically in a linear fashion underlying the epidermis and basal surface of other epithelia in mouse embryos; loss of Fras1 results in subepidermal hemorrhagic blisters and renal agenesis, and bl/bl embryos are devoid of Fras1 protein. Immunolocalization in embryonic mouse tissues, Fras1 knockout mouse generation, immunostaining of bl/bl mutant embryos Nature genetics High 12766770
2004 GRIP1 (a cytoplasmic multi-PDZ scaffolding protein) physically interacts with Fras1 and is required for the localization of Fras1 to the basal side of cells; loss of GRIP1 causes Fraser syndrome-like defects, and the eye-blebs (eb) mouse has a deletion of two coding exons of Grip1. Co-immunoprecipitation/physical interaction assay between GRIP1 and Fras1, genetic analysis of eb mouse (coding exon deletion in Grip1), loss-of-function mouse phenotype analysis Nature genetics High 14730302
2006 Fras1, QBRICK/Frem1, and Frem2 form a ternary complex in the basement membrane and reciprocally stabilize each other's basement membrane localization; loss of any single protein (Fras1, Frem1, or Frem2) depletes all three from the basement membrane zone. Immunofluorescence localization in Fraser syndrome model mice (Frem2 mutant, GRIP1 mutant, Frem1/QBRICK knockout), transfection-based secretion assay showing ternary complex formation Proceedings of the National Academy of Sciences of the United States of America High 16880404
2007 The crystal structure of GRIP1 PDZ12 tandem in complex with the Fras1 C-terminal peptide reveals that PDZ1 and PDZ2 form a supramodule, with only the peptide-binding groove of PDZ1 binding the Fras1 C-terminal peptide; PDZ1 folding strictly depends on covalent attachment to PDZ2. Crystal structure determination of GRIP1 PDZ12/Fras1 C-terminal peptide complex; domain interaction/folding analysis Journal of molecular biology High 18155042
2007 Fras1 is ultrastructurally localized within the sublamina densa of embryonic mouse epithelial basement membranes, forming clustered depositions attached to anchoring fibrils and frequently detected in close proximity to mesenchymal cells, suggesting a direct link between sublamina densa and mesenchyme. Pre-embedding immunocytochemistry with electron microscopy (immunogold/silver enhancement) in multiple embryonic mouse epithelia Archives of dermatological research Medium 17576586
2007 Loss of Fras1 results in the accumulation of Frem2 within epithelial cells, demonstrating that Fras1 is required not only as a complex component for extracellular stabilization of Frem2 but also for its proper intracellular trafficking and export from embryonic epithelial cells. Frem3 basement membrane localization remains unaffected in Fras1-null mice, demonstrating it is anchored independently of the Fras1/Frem1/Frem2 complex. Immunofluorescence localization of Frem2 and Frem3 in Fras1-null embryos; comparison of basement membrane protein retention in wild-type vs. Fras1-/- skin Matrix biology : journal of the International Society for Matrix Biology Medium 17596926
2008 Fras1 is expressed in the branching ureteric bud (UB) epithelium; in Fras1-null (bl/bl) mice, the ureteric bud fails to invade metanephric mesenchyme (replicated in organ culture), correlating with defective GDNF and GDF11 expression in renal primordia; addition of either growth factor restored bud invasion in culture. Fras1 also localizes in a glomerular basement membrane-like pattern in podocytes. In vivo analysis of bl/bl mouse kidney primordia, organ culture rescue experiment with GDNF/GDF11, immunolocalization of Fras1 in glomeruli, expression analysis of nephrogenic molecules (Hoxd11, Six2, BMP4) in mutant vs. wild-type Human molecular genetics Medium 18787044
2006 Frem1 colocalizes with Fras1 in diverse epithelial basement membranes; in Fras1-/- embryos, Frem1 is lost from the basement membrane but retained in periderm cells, indicating partial functional dependence on Fras1 for basement membrane localization. Immunofluorescence colocalization of Frem1 and Fras1 in wild-type and Fras1-/- embryonic tissues; electron microscopy showing clustered Frem1 arrangement in sublamina densa Experimental cell research Medium 17240369
2016 FRAS1 knockdown in A549 lung cancer cells reduces migration and invasion through downregulation of FAK signaling (but not Src signaling), as shown by shRNA knockdown followed by Western blot analysis. shRNA knockdown of FRAS1 in A549 cells, migration/invasion assays, Western blot for FAK and Src pathway components International journal of clinical and experimental medicine Low 25126166
2016 In Fras1(rdf) loss-of-function mice, syndactyly arises from loss of interdigital cell death (ICD); despite normal BMP ligand and receptor expression, the BMP downstream target Msx2 is downregulated in interdigital regions, suggesting Fras1-dependent epithelial-mesenchymal adhesion is required for BMP signal transmission to promote ICD. ENU-derived Fras1(rdf) nonsense allele mouse, histological analysis of interdigital cell death, in situ hybridization/immunostaining for BMP ligands, receptors, and Msx2 in limb buds Developmental dynamics : an official publication of the American Association of Anatomists Medium 26813283
2012 In zebrafish, fras1 acts in endoderm (confirmed by transplantation studies) to shape pharyngeal pouch 1 and stabilize pharyngeal skeletal development; fras1 mutants fail to generate a late-forming portion of pharyngeal pouch 1, and skeletal defects arise during late-p1 morphogenesis. Zebrafish fras1 mutant analysis, cell transplantation experiments to determine tissue of origin, temporal analysis of skeletal defects Development (Cambridge, England) Medium 22782724
2016 Fras1 and Itga8 (integrin alpha-8, expressed in complementary facial mesenchyme) function together in epithelial-mesenchymal interactions during pharyngeal pouch morphogenesis; fras1 and itga8 single and double mutants show similar craniofacial phenotypes, and using a revertible fras1 allele the critical window for fras1 function was determined to be 1.5–3 days post fertilization. Zebrafish genetics (fras1 mutant, CRISPR itga8 alleles, double mutants), revertible allele temporal analysis, expression analysis of fras1/itga8/npnt/fbn2b Developmental biology Medium 27265864
2012 Conditional podocyte-specific deletion of Fras1 leads to downregulation of FRAS1 in maturing glomeruli followed by glomerulosclerosis, demonstrating a locally required role of FRAS1 in glomerular maturation and integrity independent of skin blistering. Conditional Fras1 null allele with Cre-mediated podocyte-specific deletion in mice, histological analysis of glomeruli Genesis (New York, N.Y. : 2000) Medium 22730198
2024 CRL4-DCAF13 E3 ubiquitin ligase complex targets FRAS1 for polyubiquitination and proteasomal degradation; FRAS1 in turn promotes proliferation and migration of ovarian cancer cells through FAK signaling pathway activation. CRISPR/Cas9 knockout of DCAF13, polyubiquitination assay, proteasomal degradation assay, cell proliferation/migration assays, Western blot for FAK pathway Cellular and molecular life sciences : CMLS Medium 39367995
2023 Fraser complex proteins (Fras1, Frem1, Frem2) form anchoring cords at the dermal-epidermal junction in mouse skin; AMACO (VWA2) associates with these anchoring cords but is not required for their formation or the mutual basement membrane deposition of Fraser complex proteins. AMACO-deficient mouse generation and characterization, immunofluorescence analysis of Fraser complex protein localization in AMACO KO mice International journal of molecular sciences Medium 37047755
2020 Fras1 is expressed in choroid plexuses and specific brain regions (cortical, hippocampal, amygdalar areas) in juvenile mice; Fras1-/- mice exhibit impaired egocentric spatial memory, aberrant olfactory learning/memory, reduced fear memory, and reduced anxiety, accompanied by severely disrupted extracellular matrix organization in cortical and subcortical areas (shown by WFA immunolabeling). RT-PCR and immunostaining for Fras1 expression in brain regions, behavioral testing of Fras1-/- mice, Wisteria floribunda agglutinin (WFA) immunolabeling for ECM organization The European journal of neuroscience Medium 32333816
2013 A novel missense mutation in Fras1 (bfb allele) causes the classic blebs phenotype (epithelial-mesenchymal adhesion defects, subepidermal blistering) without embryonic lethality typical of other blebs mutants, and also produces novel palate and sternal defects, supporting a role for Fras1 in regulating signaling during organogenesis beyond adhesion. ENU mutagenesis screen, positional mapping and sequencing identifying Fras1 missense mutation, histological and phenotypic analysis of bfb mice PloS one Low 24143185

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nature genetics 190 12766769
2004 A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1. Nature genetics 120 14730302
2006 Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects. Proceedings of the National Academy of Sciences of the United States of America 110 16880404
2003 Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice. Nature genetics 107 12766770
2010 The role of Fras1/Frem proteins in the structure and function of basement membrane. The international journal of biochemistry & cell biology 76 21182980
2008 Fras1, a basement membrane-associated protein mutated in Fraser syndrome, mediates both the initiation of the mammalian kidney and the integrity of renal glomeruli. Human molecular genetics 56 18787044
2008 The Fras1/Frem family of extracellular matrix proteins: structure, function, and association with Fraser syndrome and the mouse bleb phenotype. Connective tissue research 44 18661360
2006 Overlapping and divergent localization of Frem1 and Fras1 and its functional implications during mouse embryonic development. Experimental cell research 40 17240369
2012 Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice. Human molecular genetics 38 23221805
2007 Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1. Journal of molecular biology 34 18155042
2006 Spatiotemporal distribution of Fras1/Frem proteins during mouse embryonic development. Gene expression patterns : GEP 34 17251066
2007 Basement membrane localization of Frem3 is independent of the Fras1/Frem1/Frem2 protein complex within the sublamina densa. Matrix biology : journal of the International Society for Matrix Biology 25 17596926
2006 Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with Fraser syndrome. American journal of medical genetics. Part A 24 16894541
2016 Pharyngeal morphogenesis requires fras1-itga8-dependent epithelial-mesenchymal interaction. Developmental biology 23 27265864
2012 fras1 shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development. Development (Cambridge, England) 23 22782724
2014 FRAS1 knockdown reduces A549 cells migration and invasion through downregulation of FAK signaling. International journal of clinical and experimental medicine 22 25126166
2013 Expanding the mutation spectrum for Fraser syndrome: identification of a novel heterozygous deletion in FRAS1. Gene 21 23473829
2007 Frem3, a member of the 12 CSPG repeats-containing extracellular matrix protein family, is a basement membrane protein with tissue distribution patterns distinct from those of Fras1, Frem2, and QBRICK/Frem1. Matrix biology : journal of the International Society for Matrix Biology 21 17462874
2007 Fraser and Ablepharon macrostomia phenotypes: concurrence in one family and association with mutated FRAS1. American journal of medical genetics. Part A 20 17163535
2018 The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia. Human molecular genetics 19 29618029
2008 Expression of the fras1/frem gene family during zebrafish development and fin morphogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 16 18816440
2007 Ultrastructural localization of Fras1 in the sublamina densa of embryonic epithelial basement membranes. Archives of dermatological research 15 17576586
2012 A puzzle over several decades: eye anomalies with FRAS1 and STRA6 mutations in the same family. Clinical genetics 13 22283518
2008 Differential localization profile of Fras1/Frem proteins in epithelial basement membranes of newborn and adult mice. Histochemistry and cell biology 11 18563433
2016 Syndactyly in a novel Fras1(rdf) mutant results from interruption of signals for interdigital apoptosis. Developmental dynamics : an official publication of the American Association of Anatomists 9 26813283
2022 SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population. Frontiers in genetics 7 35646073
2020 Behavioural effects of extracellular matrix protein Fras1 depletion in the mouse. The European journal of neuroscience 7 32333816
2017 Variable presentation of Fraser syndrome in two fetuses and a novel mutation in FRAS1. Congenital anomalies 7 27624506
2015 Mesenchymal expression of the FRAS1/FREM2 gene unit is decreased in the developing fetal diaphragm of nitrofen-induced congenital diaphragmatic hernia. Pediatric surgery international 6 26519041
2013 bfb, a novel ENU-induced blebs mutant resulting from a missense mutation in Fras1. PloS one 6 24143185
2012 Identification of FRAS1 as a human endometrial carcinoma-derived protein in serum of xenograft model. Gynecologic oncology 6 22842125
2024 DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway. Cellular and molecular life sciences : CMLS 5 39367995
2023 The Fraser Complex Proteins (Frem1, Frem2, and Fras1) Can Form Anchoring Cords in the Absence of AMACO at the Dermal-Epidermal Junction of Mouse Skin. International journal of molecular sciences 5 37047755
2022 Comprehensive analysis of FRAS1/FREM family as potential biomarkers and therapeutic targets in renal clear cell carcinoma. Frontiers in pharmacology 5 36249757
2021 A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer. The Prostate 5 33956343
2020 Two unrelated families with variable expression of Fraser syndrome due to the same pathogenic variant in the FRAS1 gene. American journal of medical genetics. Part A 5 31999076
2013 Segmental and restricted localization pattern of Fras1 in the developing meningeal basement membrane in mouse. Histochemistry and cell biology 5 24101214
2012 Generation of mice with a conditional null Fraser syndrome 1 (Fras1) allele. Genesis (New York, N.Y. : 2000) 5 22730198
2011 Clinical and molecular studies in two families with Fraser syndrome: a new FRAS1 gene mutation, prenatal ultrasound findings and implications for genetic counselling. Genetic counseling (Geneva, Switzerland) 4 22029163
2022 A multidisciplinary approach for prenatal diagnosis of FRASER SYNDROME-report of a novel variant in FRAS1. Taiwanese journal of obstetrics & gynecology 3 35181022
2015 A novel mutation in the FRAS1 gene in a patient with Fraser syndrome. Genetic counseling (Geneva, Switzerland) 3 26043503
2022 Whole exome sequencing identifies a novel FRAS1 mutation and aids in vitro fertilization with preimplantation genetic diagnosis in Fraser syndrome. Taiwanese journal of obstetrics & gynecology 2 35595450

Missed literature

Know a paper Affinage missed for FRAS1? Flag it for the maintainers and the community.

No submissions yet.