FILIP1L

FILIP1L is a scaffold/adaptor protein that couples the ubiquitin-proteasome system to control of transcription factors, cytoskeletal organization, and cell motility (PMID:21784850, PMID:34417201). It functions as an adaptor in targeted protein degradation: it binds Hsf1 and recruits the ubiquitin-shuttling factor HhR23A to promote Hsf1 ubiquitination, proteasomal degradation, and consequent loss of Hsf1-mediated transcription (PMID:21784850), and at centrosomes it binds PFDN1 throughout mitosis, controlling PFDN1 centrosomal localization and proteasome-dependent turnover so that loss of FILIP1L raises PFDN1 levels and produces multinucleation and cytokinesis defects (PMID:34417201). FILIP1L expression itself is tightly regulated: it is silenced by CpG island hypermethylation in cancer (PMID:23174249), transcriptionally induced by TOP2-poison chemotherapeutics through OCT1 recruitment to its promoter to mediate apoptosis (PMID:22900064), and upregulated by Prmt5-driven H4R3me2s, where it promotes β-catenin degradation (PMID:32739429). Through the FILIP1L–PFDN1 axis FILIP1L restrains Wnt/β-catenin signaling, mucin secretion, proliferation and fibrosis in epithelial tissues, with promoter methylation driving its loss in lung adenocarcinoma (PMID:36860703). FILIP1L is also a component of invadopodia that colocalizes with Tks5 and cortactin and, in a cell-cycle- and EMT-state-dependent manner, coordinates ECM degradation with migratory capacity to enable productive invasion and metastasis (PMID:41415400, PMID:42040966). In differentiating myoblasts it binds myosin to promote myofibril assembly (PMID:21832087).

1. 2011 Medium

   Established a cytoskeletal role for FILIP1L by showing it binds myosin and drives myofibril assembly, linking it to muscle differentiation.

   Evidence Co-IP and pulldown with GPBP-1, plus myoblast overexpression/knockdown with myofibril assembly readout

   PMID:21832087

   Open questions at the time

   • Binding interface to myosin not mapped
   • No in vivo validation of myofibril phenotype
   • Relationship to FILIP1L's degradation-adaptor roles unclear
2. 2011 High

   Defined FILIP1L as a degradation adaptor by showing it bridges Hsf1 to the proteasome via HhR23A to suppress Hsf1-mediated transcription, the first mechanistic role assigned to the protein.

   Evidence Yeast two-hybrid, Co-IP, ubiquitination assay with proteasome inhibitor, Hsf1 transcription reporter

   PMID:21784850

   Open questions at the time

   • The responsible E3 ligase is not identified
   • Whether FILIP1L itself confers substrate specificity beyond Hsf1 is unknown
3. 2012 Medium

   Identified the transcriptional control and apoptotic output of FILIP1L by showing TOP2-poison chemotherapeutics induce it through OCT1 to mediate cell death.

   Evidence shRNA screen, promoter ChIP for OCT1, transcription factor knockdown/relocalization, cell death assays

   PMID:22900064

   Open questions at the time

   • Downstream effectors of FILIP1L-driven apoptosis not defined
   • Specificity for TOP2 poisons versus other DNA damage unexplained mechanistically
4. 2012 Medium

   Showed FILIP1L is epigenetically silenced in cancer, establishing promoter CpG methylation as a regulatory mechanism for its expression.

   Evidence Bisulfite sequencing, pyrosequencing, demethylation rescue with RT-qPCR, tissue microarray

   PMID:23174249

   Open questions at the time

   • Isoform-specific functional differences not resolved
   • Causal link between silencing and tumor phenotype not established in this study
5. 2020 Medium

   Connected FILIP1L to Wnt signaling control by showing Prmt5/H4R3me2s upregulates FILIP1L to promote β-catenin degradation and limit cardiomyocyte hypertrophy.

   Evidence ChIP-seq, Prmt5 knockdown/overexpression/inactive mutant, β-catenin degradation and hypertrophy assays

   PMID:32739429

   Open questions at the time

   • Mechanism by which FILIP1L promotes β-catenin degradation not defined
   • Direct vs indirect role in the destruction complex unknown
6. 2021 High

   Established FILIP1L's mitotic function by showing it controls centrosomal PFDN1 localization and proteasomal turnover, preventing multinucleation and aneuploidy, with in vivo loss causing colonic hyperplasia.

   Evidence Reciprocal Co-IP, time-lapse imaging, 3D cultures, colon-specific knockout mice, xenografts, proteasome inhibitor

   PMID:34417201

   Open questions at the time

   • E3 ligase mediating PFDN1 degradation unidentified
   • Structural basis of FILIP1L–PFDN1 binding not resolved
7. 2021 Medium

   Placed FILIP1L downstream of TGF-β2-induced apoptosis as a suppressor of EMT, ECM synthesis, and migration in lens epithelial cells.

   Evidence RNA-seq, siRNA, overexpression, EMT/ECM marker Westerns, migration and flow cytometry assays

   PMID:34666037

   Open questions at the time

   • Molecular intermediaries between FILIP1L and EMT markers undefined
   • Single cell-type context
8. 2022 Medium

   Extended the FILIP1L–PFDN1 axis to lung adenocarcinoma, linking FILIP1L loss to Wnt/β-catenin activation, mucin/fibrosis phenotypes, and smoking-induced promoter methylation.

   Evidence RNA-seq of syngeneic allografts, lung-specific knockout mice, xenografts, methylation analysis

   PMID:36860703

   Open questions at the time

   • Direct mechanism linking PFDN1 to Wnt activation not established
   • Causality of smoking-induced methylation in vivo not formally proven
9. 2025 Medium

   Identified FILIP1L as an invadopodia component coordinating ECM degradation with migration in a cell-cycle- and EMT-state-dependent manner to enable invasion.

   Evidence Bulk RNA-seq, knockdown, colocalization with Tks5/cortactin, ECM degradation, migration and 3D spheroid invasion assays, cell cycle sorting (preprint)

   PMID:41415400

   Open questions at the time

   • Mechanism by which FILIP1L balances degradation vs migration unknown
   • Preprint, single lab
10. 2026 Medium

    Demonstrated in vivo that FILIP1L promotes productive metastatic colonization, integrating invadopodia activity with migratory states.

    Evidence Mouse in vivo metastasis model with knockdown, bulk RNA-seq, cell cycle sorting (preprint)

    PMID:42040966

    Open questions at the time

    • Molecular effectors at metastatic sites undefined
    • Preprint, overlaps with companion study
11. 2025 Low

    Reported mitochondrial localization of endogenous FILIP1L, raising an unresolved compartment-specific function.

    Evidence Immunofluorescence and confocal colocalization with TOM20

    PMID:40206462

    Open questions at the time

    • Single colocalization experiment with no functional consequence demonstrated
    • Not independently confirmed
    • Relationship to centrosomal/invadopodial roles unknown

• How FILIP1L mechanistically selects its degradation substrates and which E3 ligase machinery it engages remain unresolved across its Hsf1, PFDN1, and β-catenin functions.
• No E3 ligase identified for any FILIP1L-directed degradation event
• No structural model of FILIP1L or its binding interfaces
• Mechanism unifying its degradation-adaptor and invadopodia roles unknown