FBLN2

FBLN2 encodes a secreted extracellular matrix glycoprotein whose multi-domain architecture — comprising anaphylatoxin-related segments, calcium-binding EGF-like repeats, and a C-terminal fibulin-type module — enables it to function as a signaling scaffold that modulates TGF-β, BMP, and AKT/FAK pathways in diverse developmental and disease contexts (PMID:7806230, PMID:30118321, PMID:38970771, PMID:40168772). Alternative splicing of exon 9 controls an N-glycosylation site critical for proper folding, stability, and secretion; loss of this glycosylation produces misfolded protein that accumulates intracellularly, reducing extracellular FBLN2 and promoting colorectal cancer cell adhesion and migration (PMID:40400104). FBLN2 binds vitronectin and negatively regulates its expression, suppressing FAK-mediated fibrotic and migratory responses in fibroblasts, and acts as a tumor suppressor in gastric cancer by downregulating the TGFβ/TGIF2 axis and conferring anoikis sensitivity (PMID:36608640, PMID:40168772, PMID:38332530). In zebrafish, Fbln2 is required for BMP-dependent cranial neural crest chondrogenesis and regulates epicardial cell state transitions during cardiac regeneration through a Fbln2–Nupr1b effector axis (PMID:38970771, PMID:41776059).

1. 1994 High

   Establishing the molecular identity of FBLN2 resolved the domain architecture of this extracellular matrix protein, revealing a modular structure of anaphylatoxin repeats, calcium-binding EGF-like repeats, and a fibulin C-terminal module that implied diverse binding capabilities.

   Evidence Human cDNA cloning, sequencing, Northern blot, and chromosomal mapping to 3p24-p25

   PMID:7806230

   Open questions at the time

   • No binding partners identified at this stage
   • No functional role established
   • Protein tertiary structure not determined
2. 2018 Medium

   Demonstrating that Fbln2 activates TGF-β1 signaling — and is itself post-transcriptionally regulated by miR-192-5p — established the first signaling pathway placement for FBLN2 as an upstream activator of TGF-β1.

   Evidence Dual-luciferase reporter assay validating miR-192-5p targeting of Fbln2 3′-UTR, siRNA knockdown with TGF-β1 pathway readouts in CUMS mouse model

   PMID:30118321

   Open questions at the time

   • Mechanism by which FBLN2 activates TGF-β1 signaling not resolved
   • Single disease context (depression model)
   • No direct FBLN2–TGF-β1 receptor interaction shown
3. 2021 Medium

   Identifying FBLN2 as a neuron-secreted factor that enhances cancer cell migration revealed a paracrine role for FBLN2 in the tumor microenvironment and linked its secretion to Ndrg4 loss in enteric neurons.

   Evidence Ndrg4 knockout mouse, secretome proteomics, indirect co-culture migration assays with intestinal organoids

   PMID:33890711

   Open questions at the time

   • Receptor or adhesion molecule mediating FBLN2-driven migration not identified
   • No direct FBLN2 gain-of-function in neurons tested
4. 2022 Medium

   Demonstrating that FBLN2 physically binds vitronectin and suppresses FAK signaling provided the first direct binding partner and a downstream effector pathway for FBLN2 in fibrotic responses.

   Evidence Co-immunoprecipitation of FBLN2–vitronectin, siRNA knockdown with VTN rescue in TGF-β1-treated MRC-5 lung fibroblasts

   PMID:36608640

   Open questions at the time

   • Binding domain on FBLN2 for vitronectin not mapped
   • Reciprocal co-IP not explicitly described
   • Single cell type tested
5. 2022 Medium

   Single-cell profiling established Fbln2 as a marker of a profibrotic, myofibroblastic hepatic stellate cell subpopulation that expands in alcoholic hepatitis, positioning FBLN2 in liver fibrosis biology.

   Evidence scRNA-seq, FACS, Lrat-Cre lineage tracing in mouse models of alcoholic hepatitis

   PMID:36181700

   Open questions at the time

   • Whether FBLN2 is functionally required for the profibrotic phenotype or merely a marker is untested
   • No FBLN2 loss-of-function in HSCs
6. 2024 Medium

   Genetic knockout of fbln2 in zebrafish revealed its requirement for BMP-dependent cranial neural crest chondrogenesis, establishing a developmental function and connecting FBLN2 to BMP signaling.

   Evidence CRISPR/Cas9 fbln2 knockout in zebrafish with craniofacial phenotyping, BMP pathway analysis, proliferation and apoptosis assays

   PMID:38970771

   Open questions at the time

   • Mechanism by which FBLN2 activates BMP signaling unknown
   • Whether this role is conserved in mammals not tested
7. 2024 Medium

   Placing FBLN2 downstream of AKT in gastric cancer anoikis resistance — where ITGBL1 suppresses FBLN2 via AKT — established FBLN2 as a tumor-suppressive effector whose loss confers anchorage-independent survival.

   Evidence ITGBL1 overexpression/knockdown with AKT inhibitor rescue, in vitro anoikis assays and in vivo tumor models

   PMID:38332530

   Open questions at the time

   • Direct molecular mechanism of AKT-mediated FBLN2 suppression unclear (transcriptional vs. post-translational)
   • Single cancer type
8. 2025 High

   Demonstrating that alternative splicing of exon 9 removes an N-glycosylation site essential for FBLN2 folding, stability, and secretion resolved a post-translational mechanism controlling extracellular FBLN2 availability and its tumor-suppressive function in colorectal cancer.

   Evidence Glycosylation site mutagenesis, protein stability and secretion assays, cell adhesion and migration assays in colorectal cancer cells

   PMID:40400104

   Open questions at the time

   • Splicing regulators controlling exon 9 inclusion not identified
   • Whether this mechanism operates in non-cancer tissues unknown
9. 2025 Medium

   Genetic gain- and loss-of-function studies showed FBLN2 suppresses gastric cancer via the TGFβ/TGIF2 axis, converging with earlier TGF-β pathway placement and solidifying FBLN2 as a tumor suppressor.

   Evidence FBLN2 overexpression and CRISPR knockout in GC cells, RNA-seq pathway analysis, in vivo xenograft models

   PMID:40168772

   Open questions at the time

   • Mechanism by which FBLN2 downregulates TGIF2 not dissected
   • Whether FBLN2 acts extracellularly or intracellularly on this axis unresolved
10. 2026 High

    Epistasis experiments in zebrafish cardiac regeneration identified Nupr1b as a downstream effector of Fbln2 in epicardial cell state transitions, establishing a Fbln2–Nupr1b axis governing myofibroblast abundance during heart repair.

    Evidence Fbln2 gain/loss-of-function, epicardial-specific Nupr1b overexpression rescue in zebrafish cardiac injury model

    PMID:41776059

    Open questions at the time

    • Intermediate signaling steps between FBLN2 and Nupr1b activation unknown
    • Mammalian conservation of this axis not demonstrated

• The receptor(s) and cell-surface signaling complexes through which secreted FBLN2 activates or modulates TGF-β, BMP, and other pathways remain unidentified, as does a high-resolution structural model of the protein.
• No FBLN2 receptor identified
• No crystal or cryo-EM structure available
• Splicing regulators of exon 9 unknown