FBLN2

Fibulin-2 (FBLN2) is a secreted, multi-domain extracellular matrix glycoprotein built from an N-terminal cysteine-rich and acidic region, three anaphylatoxin-related segments, ten EGF-like repeats (nine calcium-binding), and a fibulin-type C-terminal domain (PMID:7806230). Its proper folding, stability, and secretion depend on N-glycosylation: cancer-associated exclusion of exon 9 removes a single N-glycosylation site and causes misfolding and reduced secretion, depleting FBLN2 from the tumor ECM (PMID:40400104). As a matrix component, FBLN2 regulates fibrogenic and developmental signaling: it physically interacts with vitronectin and negatively regulates it, attenuating TGF-β1-driven fibroblast migration, proliferation, and fibrosis through reduced FAK signaling (PMID:36608640), while in the mouse hippocampus FBLN2 positively drives TGF-β1 signaling and is held in check post-transcriptionally by miR-192-5p (PMID:30118321). In development and regeneration, FBLN2 supports cranial neural crest chondrogenesis via BMP signaling (PMID:38970771) and balances fibrosis versus regeneration in the injured zebrafish heart by controlling epicardial myofibroblast abundance through a Fbln2→Nupr1b axis (PMID:41776059). In cancer, FBLN2 has context-dependent roles, acting as a downstream effector of AKT that suppresses anoikis resistance and as a suppressor of gastric cancer proliferation and invasion via the TGFβ/TGIF2 axis (PMID:38332530, PMID:40168772).

1. 1994 High

   Established the primary structure and domain organization of fibulin-2, defining it as a calcium-binding, EGF-repeat-containing matrix glycoprotein and providing the framework for all later functional studies.

   Evidence cDNA sequencing, Northern blot, and in situ hybridization with chromosomal mapping

   PMID:7806230

   Open questions at the time

   • No functional role assigned to individual domains
   • No binding partners identified at this stage
2. 2018 Medium

   Identified post-transcriptional control of FBLN2 by miR-192-5p and placed FBLN2 as a positive regulator of TGF-β1 signaling in the brain, linking the matrix protein to neuronal/cognitive phenotypes.

   Evidence Dual-luciferase reporter assay, miRNA mimic/inhibitor, hippocampal electrophysiology and behavioral assays in a CUMS mouse model

   PMID:30118321

   Open questions at the time

   • Direction of TGF-β1 regulation (positive here) differs from fibrosis context
   • Mechanism by which a secreted ECM protein modulates hippocampal signaling unresolved
3. 2021 Medium

   Positioned FBLN2 in cancer cell behavior as a downstream effector of AKT signaling that suppresses anoikis resistance, and as an ENS-secreted factor that can promote colorectal cancer migration.

   Evidence siRNA/overexpression with anoikis and xenograft assays; Ndrg4 knockout mice with organoid co-culture and proteomics

   PMID:33890711 PMID:38332530

   Open questions at the time

   • Opposing pro- and anti-tumor roles across tissues not reconciled
   • No direct receptor or signaling intermediary identified
4. 2022 Medium

   Defined a vitronectin-FAK fibrosis axis and identified an Fbln2-marked profibrotic hepatic stellate cell subpopulation, connecting FBLN2 to TGF-β1-driven fibrogenesis.

   Evidence Reciprocal co-IP and rescue in fibroblasts; scRNA-seq with Lrat-Cre lineage tracing in alcoholic hepatitis

   PMID:36181700 PMID:36608640

   Open questions at the time

   • Whether the Fbln2+ HSC marker reflects a functional role for FBLN2 protein not established
   • VTN-FAK mechanism not confirmed in vivo
5. 2024 Medium

   Demonstrated a developmental requirement for FBLN2 in craniofacial chondrogenesis via BMP signaling and a role in maintaining basal/myoepithelial mammary cell identity.

   Evidence CRISPR/Cas9 fbln2 knockout in zebrafish with BMP pathway analysis; siRNA in EpH4 mammary cells with marker readouts

   PMID:38970771 PMID:39110274

   Open questions at the time

   • How FBLN2 mechanistically activates BMP signaling unknown
   • Mammary findings rest on marker expression only (Low confidence)
6. 2025 Medium

   Provided biochemical mechanism linking a cancer-associated splicing event to FBLN2 dysfunction, showing exon 9 exclusion removes an N-glycosylation site needed for folding and secretion, and identified the TGFβ/TGIF2 axis for its tumor-suppressive activity.

   Evidence Splicing/glycosylation/secretion assays with ECM analysis in colorectal cancer; FBLN2 knockout/overexpression with RNA-seq and KEGG in gastric cancer cells

   PMID:40168772 PMID:40400104

   Open questions at the time

   • Structural basis of misfolding not resolved
   • Direct molecular target downstream of TGIF2 not defined
7. 2026 High

   Established Fbln2 as a regulator of epicardial activation in cardiac regeneration acting through Nupr1b, demonstrating genetic epistasis that balances fibrosis and regeneration after injury.

   Evidence Genetic dosage manipulation with epicardial-specific nupr1b overexpression rescue in zebrafish cardiac injury

   PMID:41776059

   Open questions at the time

   • How secreted Fbln2 controls nuclear Nupr1b expression mechanistically unknown
   • Conservation of the axis in mammalian heart untested

• How a single secreted ECM glycoprotein produces opposing context-dependent outputs on TGF-β signaling and tumor behavior across tissues remains unresolved.
• No unifying receptor or signaling mechanism identified across contexts
• Domain-level structure-function mapping to specific signaling partners absent