Affinage

FOCAD

Focadhesin · UniProt Q5VW36

Length
1801 aa
Mass
200.1 kDa
Annotated
2026-06-09
16 papers in source corpus 9 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOCAD (focadhesin) is a tumor suppressor and cytoskeleton-associated protein whose principal mechanistic role is to maintain the integrity of the cytoplasmic SKI mRNA surveillance and ribosome-rescue machinery (PMID:22427331, PMID:35864190). At focal adhesions it co-localizes and physically interacts with vinculin (PMID:22427331), and at centrosomes it binds tubulins and is recruited to microtubules via SLAIN2, reducing microtubule assembly rates and modulating G2/M progression (PMID:31473790). Its dominant characterized function is post-transcriptional stabilization of the SKI complex: FOCAD is required to sustain levels of the RNA helicase SKIC2 and its cofactor SKIC3, and FOCAD loss destabilizes this complex, impairing degradation of aberrant mRNAs and disrupting hepatocyte homeostasis (PMID:35864190). Because SKI-dependent surveillance feeds into ribosome rescue, FOCAD-deleted cells become dependent on parallel quality-control routes, generating synthetic lethal vulnerabilities to TUT7/DIS3L2 and to the HBS1L/PELO ribosome-rescue complex, the latter exploited by the molecular-glue HBS1L degrader TNG961 (PMID:39235218, PMID:41101730, PMID:42001523). FOCAD transcription is negatively controlled by NRF2 through an NRF2–RPA1–ARE complex and by EGR1 binding the FOCAD promoter, and FOCAD promotes FAK activity to sensitize cells to cysteine-deprivation ferroptosis (PMID:32898818, PMID:35788362).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2012 High

    Established FOCAD's first molecular context by showing it is a focal adhesion protein and acts as a tumor suppressor, framing why its loss matters in cancer.

    Evidence Reciprocal co-IP and immunofluorescence with vinculin plus colony/migration/invasion assays and orthotopic glioma xenografts

    PMID:22427331

    Open questions at the time
    • Mechanism linking focal adhesion localization to tumor suppression not defined
    • No structural basis for vinculin interaction
  2. 2019 Medium

    Extended FOCAD's cytoskeletal role to the microtubule system, addressing how it might influence cell division.

    Evidence Yeast two-hybrid, pull-down, and co-localization identifying tubulins and SLAIN2; cell-cycle analysis showing G2/M-peaked levels

    PMID:31473790

    Open questions at the time
    • PLK1 phosphorylation inferred, not directly mutagenized
    • Functional consequence of reduced microtubule assembly for tumor suppression unresolved
  3. 2020 Medium

    Identified upstream transcriptional repression by NRF2 and a downstream FAK-driven metabolic role linking FOCAD to ferroptosis sensitivity.

    Evidence Reporter assays, ChIP of NRF2–RPA1–ARE complex, FAK activity and metabolic assays, in vivo combination treatment

    PMID:32898818

    Open questions at the time
    • Single lab; how FOCAD promotes FAK activity mechanistically not defined
    • Connection between FAK axis and other FOCAD functions unclear
  4. 2022 High

    Defined FOCAD's core molecular function as post-transcriptional stabilization of the SKI mRNA surveillance complex, explaining a tissue homeostasis phenotype.

    Evidence CRISPR-Cas9 KO, patient primary cells, zebrafish phenocopy, protein quantification of SKIC2/SKIC3; hepatocyte functional assays

    PMID:35864190

    Open questions at the time
    • Direct binding interface between FOCAD and SKI components not structurally resolved
    • How FOCAD prevents SKI complex turnover mechanistically unknown
  5. 2022 Medium

    Identified EGR1 as a second transcriptional repressor of FOCAD and its intronic miR-491-5p.

    Evidence ChIP and fluorescence reporter assay confirming direct promoter binding

    PMID:35788362

    Open questions at the time
    • Physiological context of EGR1 regulation not established
    • Interplay between EGR1 and NRF2 repression unresolved
  6. 2024 High

    Showed FOCAD loss creates a druggable synthetic lethality with TUT7/DIS3L2, converting the SKI-stabilization function into a therapeutic strategy.

    Evidence Isogenic CRISPR KO, FOCAD re-expression rescue, TUT4/7 inhibitor treatment in vitro and in vivo

    PMID:39235218

    Open questions at the time
    • Full set of mRNA substrates rerouted to TUT7/DIS3L2 not catalogued
  7. 2025 High

    Demonstrated a second synthetic lethality with the HBS1L/PELO ribosome-rescue complex, linking FOCAD's SKI defect to ribosomal stalling resolution.

    Evidence Combinatorial and genome-wide CRISPR screens in isogenic cells, FOCAD re-expression rescue, in vivo tumor assays

    PMID:41101730

    Open questions at the time
    • Precise stalled-mRNA species accumulating in FOCAD-deleted cells not defined
  8. 2026 High

    Provided structural and pharmacologic proof-of-concept by developing a molecular-glue degrader that exploits the FOCAD-loss HBS1L dependency.

    Evidence Cryo-EM of HBS1L–CRBN–compound complex, biochemical ubiquitination, selectivity profiling, in vivo tumor growth

    PMID:42001523

    Open questions at the time
    • Clinical translation not addressed
    • Selectivity in FOCAD-intact tissues over chronic dosing unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FOCAD physically stabilizes the SKI complex and whether its focal adhesion/microtubule roles are mechanistically linked to its mRNA surveillance function remain unresolved.
  • No atomic structure of FOCAD bound to SKI components
  • Unclear whether vinculin/tubulin binding and SKI stabilization are independent activities

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005815 microtubule organizing center 2 GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3
Partners
SKIC2SKIC3SLAIN2TUBB6VCL
Complex memberships
SKI complex (SKIC2/SKIC3)focal adhesion

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 FOCAD (KIAA1797/focadhesin) co-localizes with vinculin at focal adhesions, and physical interaction between FOCAD and vinculin was demonstrated by co-immunoprecipitation, establishing FOCAD as a focal adhesion complex protein. Co-immunoprecipitation, immunofluorescence co-localization Brain Medium 22427331
2012 Ectopic re-expression of FOCAD in glioma cells with homozygous FOCAD deletion significantly decreased colony formation, migration, and invasion in vitro, and reduced tumor volume in an orthotopic xenograft mouse model, establishing a tumor suppressor function. Loss-of-function / gain-of-function in vitro assays (colony formation, migration, invasion), in vivo orthotopic xenograft model Brain High 22427331
2019 Yeast two-hybrid screening and pull-down assays identified tubulin beta-6 and other tubulin family members as FOCAD-interacting partners; FOCAD co-localized with tubulins at centrosomes/centrioles and reduced microtubule assembly rates. Yeast two-hybrid screen, pull-down assays, immunofluorescence co-localization Acta neuropathologica Medium 31473790
2019 FOCAD was recruited to microtubules via its interaction partner SLAIN motif family member 2 (SLAIN2), and FOCAD levels peaked in G2/M phase, influencing G2/M progression potentially via polo-like kinase 1 phosphorylation. Pull-down assays, cell-cycle analysis, co-localization Acta neuropathologica Medium 31473790
2020 NRF2 negatively regulates FOCAD transcription via a NRF2–RPA1–ARE complex. FOCAD in turn promotes FAK activity, which enhances sensitivity to cysteine deprivation-induced ferroptosis by promoting the TCA cycle and mitochondrial ETC Complex I activity. Transcriptional reporter assays, chromatin immunoprecipitation, FAK activity assays, metabolic assays, in vitro and in vivo combination drug treatment Redox biology Medium 32898818
2022 FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of RNA helicase SKIC2 and its cofactor SKIC3 (components of the SKI complex), leading to impaired mRNA degradation; this was demonstrated in patient primary cells and CRISPR-Cas9 knockout human hepatic cell lines. CRISPR-Cas9 knockout, patient primary cell analysis, zebrafish phenocopy model, Western blot/protein quantification Nature genetics High 35864190
2022 FOCAD knockout hepatocytes exhibited lowered albumin expression, signs of persistent injury, and CCL2 overproduction, indicating FOCAD is required for hepatocyte homeostasis. CRISPR-Cas9 knockout, gene expression analysis, functional hepatocyte assays Nature genetics Medium 35864190
2022 EGR1 binds the FOCAD promoter and negatively regulates FOCAD (and its intronic miR-491-5p) at the transcriptional level, as confirmed by fluorescence reporter gene assay and chromatin immunoprecipitation. Chromatin immunoprecipitation (ChIP), fluorescence reporter gene assay, bioinformatic analysis Progress in biophysics and molecular biology Medium 35788362
2024 FOCAD loss posttranscriptionally destabilizes the SKI complex (reducing SKIC2/SKIC3 levels), creating synthetic lethality with TUT7 and DIS3L2; reintroduction of FOCAD restores the SKI complex and rescues sensitivity to TUT4/7 inhibitors, demonstrating that TUT7 dependency is mechanistically driven by FOCAD loss. CRISPR knockout, isogenic cell lines, FOCAD re-expression rescue, TUT4/7 inhibitor treatment, in vitro and in vivo proliferation assays Molecular cancer therapeutics High 39235218
2025 FOCAD loss creates synthetic lethality with HBS1L (a ribosome-rescue GTPase and PELO binding partner); HBS1L loss in FOCAD-deleted cells leads to translational arrest and unfolded protein response activation. FOCAD re-expression rescued HBS1L dependency, and FOCAD knockout rendered FOCAD-intact cells HBS1L-dependent, establishing that FOCAD and the HBS1L/PELO complex together resolve aberrant mRNA-induced ribosomal stalling. Combinatorial CRISPR screen, genome-wide CRISPR screen in isogenic cells, FOCAD re-expression rescue, in vivo tumor growth assays Biochimica et biophysica acta. Molecular cell research High 41101730
2026 Cryo-EM structures guided development of TNG961, a molecular glue degrader that promotes HBS1L–CRBN–compound complex formation and E3-ligase-dependent HBS1L ubiquitination and degradation, confirming that disruption of the HBS1L/PELO complex in FOCAD-deleted cells induces translational arrest and unfolded protein response activation. Cryo-EM structural determination, biochemical ubiquitination assays, proteome selectivity profiling, in vitro and in vivo tumor growth assays Cancer discovery High 42001523
2021 PRICKLE1 and FOCAD proteins co-localize in murine cranial base chondrocytes, and this co-localization is disrupted in Prickle1 hypomorphic mutants, placing FOCAD in a PRICKLE1-dependent pathway governing cranial base morphology. Immunofluorescence co-localization in mouse tissue, genetic mouse model analysis Frontiers in genetics Low 34434215

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 NRF2 regulates the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via FOCAD-FAK signaling pathway. Redox biology 115 32898818
2012 KIAA1797/FOCAD encodes a novel focal adhesion protein with tumour suppressor function in gliomas. Brain : a journal of neurology 49 22427331
2015 Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development. The Journal of pathology 28 25712196
2022 Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis. Nature genetics 23 35864190
2019 FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas. Acta neuropathologica 19 31473790
2010 Bivariate genetic association of KIAA1797 with heart rate in American Indians: the Strong Heart Family Study. Human molecular genetics 18 20601674
2021 Identification of the Novel Tumor Suppressor Role of FOCAD/miR-491-5p to Inhibit Cancer Stemness, Drug Resistance and Metastasis via Regulating RABIF/MMP Signaling in Triple Negative Breast Cancer. Cells 13 34685504
2021 PRICKLE1 × FOCAD Interaction Revealed by Genome-Wide vQTL Analysis of Human Facial Traits. Frontiers in genetics 8 34434215
2024 Targeting the Synthetic Lethal Relationship between FOCAD and TUT7 Represents a Potential Therapeutic Opportunity for TUT4/7 Small-Molecule Inhibitors in Cancer. Molecular cancer therapeutics 5 39235218
2022 FOCAD/miR-491-5p, downregulated by EGR1, function as tumor suppressor by inhibiting the proliferation and migration of gastric cancer cells. Progress in biophysics and molecular biology 3 35788362
2025 Tumor suppressor collateral damage screens reveal mRNA homeostasis protein HBS1L as a novel vulnerability in ch9p21 driven FOCAD deleted cancer. Biochimica et biophysica acta. Molecular cell research 1 41101730
2025 FOCAD Gene Defect Resulting in Rapidly Progressing Neonatal Liver Cirrhosis Requiring Transplant. Cureus 1 41189834
2022 FOCAD Indel in a Family With Juvenile Polyposis Syndrome. Journal of pediatric gastroenterology and nutrition 1 35622075
2026 A novel homozygous splice-site variant in the FOCAD gene causing infantile liver cirrhosis and neutropenia: expanding disease phenotype and successful surgical treatment. Frontiers in medicine 0 41608453
2026 TNG961 is a selective oral HBS1L molecular glue degrader for the treatment of FOCAD-deleted cancers. Cancer discovery 0 42001523
2025 A Rare Case of Neonatal Cholestasis Linked to FOCAD Gene Variants: Exploring the Variable Phenotypic Presentation and Its Implications. Case reports in genetics 0 40662096

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