Affinage

FBLN1

Fibulin-1 · UniProt P23142

Length
703 aa
Mass
77.2 kDa
Annotated
2026-06-09
18 papers in source corpus 7 papers cited in narrative 7 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

FBLN1 is a secreted extracellular matrix glycoprotein essential for vascular wall integrity, with developmental and skeletal regulatory roles that operate through TGF-β/Smad and Fgf8 signaling (PMID:16338003, PMID:33610427, PMID:38397376). During limb development it is deposited in digit-associated ECM, and its splice variants differ in matrix incorporation, with the FBLN1-D variant showing altered ECM assembly in synpolydactyly patient fibroblasts (PMID:11836357). Genetic deletion in mice is lethal and identifies FBLN1 as a structural component of blood vessel walls (PMID:16338003). FBLN1 acts as a context-dependent modulator of TGF-β/Smad signaling: it promotes chondrocyte proliferation and Col2 upregulation by increasing Smad2 phosphorylation (PMID:33610427), yet in injured lung epithelium it suppresses TGF-β/Smad activity to limit ferroptosis (PMID:39671383), indicating its signaling output depends on cellular context. In skeletal tissue FBLN1 is a negative regulator of mineralization, acting upstream of Fgf8 signaling, as zebrafish mutants show increased mineralization and collagen biosynthesis gene upregulation (PMID:38397376). FBLN1 expression is post-transcriptionally constrained: m6A methylation in its 3'UTR is read by YTHDF2 to destabilize the transcript and, together with miR-615-3p, suppress osteogenic differentiation (PMID:38353178). A destabilizing missense variant (p.Arg550His) reduces FBLN1 protein levels and, in combination with an ARHGAP31 variant, impairs Cdc42 activity and activates MAPK/ERK signaling (PMID:36176297).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2002 Medium

    Established that FBLN1 is incorporated into developing limb ECM in a splice-variant-specific manner, framing distinct functional roles for the C and D isoforms in matrix assembly.

    Evidence Immunolocalization in developing limb ECM and biochemical fractionation of FBLN1-C/D variants from synpolydactyly patient fibroblasts and conditioned medium

    PMID:11836357

    Open questions at the time
    • Molecular basis for differential variant incorporation not defined
    • No reconstitution of ECM assembly
    • Link between altered incorporation and synpolydactyly phenotype indirect
  2. 2005 Medium

    Demonstrated that FBLN1 is genetically essential for blood vessel wall integrity and defined its placental expression, resolving whether FBLN1 drives placental hyperplasia (it does not).

    Evidence Homozygous knockout mouse with lethal vascular phenotype, in situ expression, and a non-rescuing placental hyperplasia model

    PMID:16338003

    Open questions at the time
    • Molecular mechanism of vascular wall defect unresolved
    • Lethality precludes tissue-specific functional dissection
    • Negative placental result leaves the hyperplasia cause unidentified
  3. 2021 Medium

    Connected FBLN1 to active Smad2 signaling, showing it promotes chondrocyte proliferation rather than acting purely as a structural matrix protein.

    Evidence Adenoviral FBLN1 overexpression in chondrocytes with EdU proliferation, pSmad2/Col2 Western blotting, and pSmad2 inhibitor rescue

    PMID:33610427

    Open questions at the time
    • Mechanism linking secreted FBLN1 to intracellular Smad2 phosphorylation unknown
    • No direct receptor or binding partner identified
    • Single overexpression system
  4. 2022 Medium

    Showed a missense variant destabilizes FBLN1 protein and synergizes with ARHGAP31 mutation to disrupt Cdc42 and MAPK/ERK signaling, linking FBLN1 dosage to intracellular signaling defects.

    Evidence Wild-type/mutant FBLN1 transfection with stability immunoblots, viability/apoptosis assays, Cdc42 activity assay, and ARHGAP31 co-transfection

    PMID:36176297

    Open questions at the time
    • Effects only manifest in combination with ARHGAP31 variant
    • Mechanism connecting extracellular FBLN1 to Cdc42 not defined
    • Single in vitro lab without in vivo confirmation
  5. 2024 Medium

    Identified post-transcriptional control of FBLN1 by m6A/YTHDF2 and miR-615-3p, explaining how FBLN1 levels are tuned to govern osteogenic differentiation.

    Evidence m6A site mutation, YTHDF2 gain/loss, miR-615-3p manipulation, mRNA stability and osteogenic assays in WJCMSCs, plus in vivo bone regeneration

    PMID:38353178

    Open questions at the time
    • m6A writer/eraser controlling the site not identified
    • Whether this regulation operates in vascular or skeletal tissues unknown
    • Single lab
  6. 2024 Medium

    Defined a context-dependent role in which FBLN1 antagonizes TGF-β/Smad signaling to limit ferroptosis, contrasting with its Smad2-promoting role in chondrocytes.

    Evidence FBLN1 and TGF-β1 overexpression in LPS-treated MLE-12 lung epithelial cells with TGF-β/Smad and ferroptosis marker readouts

    PMID:39671383

    Open questions at the time
    • Direct biochemical interaction with TGF-β/Smad not demonstrated
    • Reconciliation with Smad2-promoting role in cartilage unresolved
    • In vitro overexpression only
  7. 2024 Medium

    Placed FBLN1 as a negative regulator of skeletal mineralization upstream of Fgf8, establishing an in vivo developmental signaling axis.

    Evidence CRISPR/Cas9 fbln1 zebrafish mutants with micro-CT skeletal phenotyping and bulk RNA-seq pathway analysis

    PMID:38397376

    Open questions at the time
    • Direct mechanism linking FBLN1 to Fgf8 downregulation not defined
    • Mineralization phenotype not yet linked to human skeletal disease
    • Single model organism

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FBLN1 produces opposite effects on Smad signaling in different tissues, and what receptors or matrix partners transduce its secreted signal, remains unresolved.
  • No defined receptor or signaling co-factor for FBLN1
  • Context determinants of Smad2 promotion vs TGF-β/Smad antagonism unknown
  • No structural basis for variant-driven instability or splice-variant ECM behavior

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005576 extracellular region 2 GO:0031012 extracellular matrix 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1474244 Extracellular matrix organization 1

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 FBLN1 protein is expressed in the extracellular matrix in association with digits during developing limb formation; the FBLN1-D splice variant, but not the FBLN1-C splice variant, shows altered incorporation into ECM and conditioned medium in fibroblasts from patients with synpolydactyly, suggesting splice-variant-specific ECM roles. Immunolocalization of FBLN1 in developing limb ECM; analysis of FBLN1-C and FBLN1-D splice variant levels in patient fibroblast ECM and conditioned medium Journal of medical genetics Medium 11836357
2005 Fbln1 null mice are lethal, establishing FBLN1 as an essential component of blood vessel walls; Fbln1 is expressed in spongiotrophoblast, endothelia of large fetal blood vessels, and a subset of giant cells in the mouse placenta, but Fbln1 alone is not the key cause of placental hyperplasia phenotypes in a congenic interspecies hybrid model. Homozygous targeted gene deletion (knockout mouse), in situ expression analysis, rescue experiment attempting to normalize Fbln1 expression in hyperplastic placentas Placenta Medium 16338003
2021 FBLN1 promotes chondrocyte proliferation in knee cartilage by increasing phosphorylation of Smad2 and upregulating Col2; inhibition of pSmad2 abolishes the FBLN1-driven proliferation effect. Adenoviral overexpression of FBLN1 in isolated chondrocytes, EdU proliferation assay, Western blotting for pSmad2 and Col2, pharmacological inhibition of pSmad2 Journal of orthopaedic science Medium 33610427
2024 FBLN1 overexpression inhibits the TGF-β/Smad signaling pathway (decreased TGF-β and p-Smad protein levels) and thereby reduces ferroptosis markers (MDA, lipid ROS, Fe2+) in LPS-treated lung epithelial cells; FBLN1 and TGF-β have antagonistic roles in regulating ferroptosis. Overexpression of FBLN1 and TGF-β1 in MLE-12 cells treated with LPS, Western blotting for TGF-β/Smad pathway proteins and ferroptosis markers, cell viability assay PloS one Medium 39671383
2024 FBLN1 mRNA stability is regulated by m6A methylation at a site in its 3'UTR; YTHDF2 binds this m6A site and induces FBLN1 mRNA instability, reducing FBLN1 expression and suppressing osteogenic differentiation of WJCMSCs. Mutation of the m6A site enhances FBLN1 mRNA stability and osteogenic differentiation. miR-615-3p also negatively regulates FBLN1 by binding its 3'UTR, and YTHDF2 facilitates miR-615-3p-mediated FBLN1 mRNA decay. m6A site mutation, YTHDF2 overexpression/knockdown, miR-615-3p gain/loss of function, mRNA stability assays, osteogenic differentiation assays in WJCMSCs, bone regeneration in vivo model Cell proliferation Medium 38353178
2022 A missense variant of FBLN1 (p.Arg550His) results in reduced protein stability and decreased FBLN1 expression. In combination with an ARHGAP31 variant, but not alone, FBLN1 mutation decreases cell viability, impairs proliferation, activates apoptosis, reduces Cdc42 activity, and activates the MAPK/ERK pathway in vitro, indicating synergistic disruption of cellular signaling. Expression vectors with wild-type and mutant FBLN1 transfected in mammalian cells; immunoblotting for protein stability and expression; cell viability (CCK-8), immunofluorescence, co-transfection with ARHGAP31 mutant; Cdc42 activity assay; Western blotting for MAPK/ERK pathway Frontiers in genetics Medium 36176297
2024 fbln1 mutant zebrafish show increased mineralization of cranial elements, altered ceratohyal angle, increased vertebral dimensions and tissue mineral density in adults, with transcriptomic upregulation of collagen biosynthesis genes and downregulation of Fgf8 signaling, placing FBLN1 as a negative regulator of skeletal mineralization upstream of Fgf8 signaling. CRISPR/Cas9-generated fbln1 zebrafish mutants, micro-CT skeletal analysis, bulk RNA-seq transcriptomics of mutant vs. wild-type Biomolecules Medium 38397376

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly. Journal of medical genetics 87 11836357
2009 Aberrant promoter methylation of FBLN-3 gene and clinicopathological significance in non-small cell lung carcinoma. Lung cancer (Amsterdam, Netherlands) 26 19913326
2010 A genomics-informed, SNP association study reveals FBLN1 and FABP4 as contributing to resistance to fleece rot in Australian Merino sheep. BMC veterinary research 20 20500888
2018 Serum FBLN1 and STK31 as biomarkers of colorectal cancer and their ability to noninvasively differentiate colorectal cancer from benign polyps. Clinica chimica acta; international journal of clinical chemistry 19 29715435
2021 Discovery and validation of FBLN1 and ANT3 as potential biomarkers for early detection of cervical cancer. Cancer cell international 14 33602229
2024 miR615-3p inhibited FBLN1 and osteogenic differentiation of umbilical cord mesenchymal stem cells by associated with YTHDF2 in a m6A-miRNA interaction manner. Cell proliferation 13 38353178
2005 Expression and functional analysis of fibulin-1 (Fbln1) during normal and abnormal placental development of the mouse. Placenta 13 16338003
1995 Localization of the human gene for fibulin-1 (FBLN1) to chromosome band 22q13.3. Cytogenetics and cell genetics 13 7842734
2021 Circ_FBLN1 promotes the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by regulating let-7i-5p/FZD4 axis and Wnt/β-catenin pathway. Journal of bioenergetics and biomembranes 11 34424449
2013 Abnormal hypermethylation and clinicopathological significance of FBLN1 gene in cutaneous melanoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 10 23907575
1994 The fibulin-1 gene (FBLN1) is located on human chromosome 22 and on mouse chromosome 15. Genomics 8 7806231
2024 The Osteoblast Transcriptome in Developing Zebrafish Reveals Key Roles for Extracellular Matrix Proteins Col10a1a and Fbln1 in Skeletal Development and Homeostasis. Biomolecules 5 38397376
2024 FBLN1 regulates ferroptosis in acute respiratory distress syndrome by reducing free ferrous iron by inhibiting the TGF-β/Smad pathway. PloS one 5 39671383
2021 FBLN1 promotes chondrocyte proliferation by increasing phosphorylation of Smad2. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 5 33610427
2024 A Bioinformatics-Based Study on Methylation Alterations of the FBLN1 Gene in Hippocampal Tissue of Alzheimer's Disease Model DKO and DTG Mice. International journal of molecular sciences 2 39201719
2022 Synergistic effects of rare variants of ARHGAP31 and FBLN1 in vitro in terminal transverse limb defects. Frontiers in genetics 2 36176297
2026 Human Papillomavirus (HPV) Infected Epithelial Cells and FBLN1+ Fibroreticular Cells Govern the Immunogenic Tumor Microenvironment in HPV-Associated Oropharyngeal Squamous Cell Carcinoma. Clinical and experimental otorhinolaryngology 0 41913707
2026 Integrated multi-omics and experimental validation reveal CSK and FBLN1 as key targets of stanozolol in accelerating atherosclerosis. Vascular pharmacology 0 42250865

Missed literature

Know a paper Affinage missed for FBLN1? Flag it for the maintainers and the community.

No submissions yet.