CASS4

UniProt ID: Q9NQ75
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

CASS4 encodes Cas scaffolding protein family member 4, also called HEPL, a Crk-associated substrate family docking protein that acts at focal adhesions and cytoskeletal adhesion sites. CASS4 links integrin-dependent adhesion sites to focal adhesion kinase/protein tyrosine kinase signaling, helping regulate focal adhesion integrity, substrate-dependent cell spreading, and cell migration. Cancer-cell studies additionally support context-specific roles in invasion and AKT pathway activation, while the Alzheimer-disease-relevant cellular mechanism remains unresolved.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, and membrane-adjacent adhesion contexts.
Reason: Accept as a core localization. CASS4/HEPL is described as a Cas-family docking scaffold with focal-adhesion localization, and the GOA experimental and family-based annotations consistently place it in cytoplasm/cytoskeleton/focal-adhesion contexts.
GO:0016477 cell migration
IBA
GO_REF:0000033 		ACCEPT
Summary: CASS4/HEPL supports migration and invasion-related adhesion signaling in Cas-family and NSCLC evidence.
Reason: Accept as part of the core phenotype of Cas-family adhesion signaling. The original HEPL paper and NSCLC studies connect CASS4/HEPL with cell spreading, migration, invasion, and focal-adhesion signaling.
GO:0005886 plasma membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, and membrane-adjacent adhesion contexts.
Reason: Accept as a core localization. CASS4/HEPL is described as a Cas-family docking scaffold with focal-adhesion localization, and the GOA experimental and family-based annotations consistently place it in cytoplasm/cytoskeleton/focal-adhesion contexts.
GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway
IBA
GO_REF:0000033 		MODIFY
Summary: The broad receptor-tyrosine-kinase signaling IBA captures adhesion-associated tyrosine kinase signaling but is too broad and points to the wrong signaling branch.
Reason: Modify to integrin-mediated signaling pathway. The direct HEPL evidence describes integrin-dependent signals at focal adhesions and regulation of FAK activity, not canonical signaling through a cell-surface receptor protein tyrosine kinase. Integrin-mediated signaling better captures the Cas-family focal-adhesion context.
GO:0005856 cytoskeleton
IEA
GO_REF:0000044 		ACCEPT
Summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, and membrane-adjacent adhesion contexts.
Reason: Accept as a core localization. CASS4/HEPL is described as a Cas-family docking scaffold with focal-adhesion localization, and the GOA experimental and family-based annotations consistently place it in cytoplasm/cytoskeleton/focal-adhesion contexts.
GO:0005925 focal adhesion
IEA
GO_REF:0000120 		ACCEPT
Summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, and membrane-adjacent adhesion contexts.
Reason: Accept as a core localization. CASS4/HEPL is described as a Cas-family docking scaffold with focal-adhesion localization, and the GOA experimental and family-based annotations consistently place it in cytoplasm/cytoskeleton/focal-adhesion contexts.
GO:0005737 cytoplasm
IDA
PMID:23001926
Overexpression and cytoplasmic accumulation of Hepl is assoc... 		ACCEPT
Summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, and membrane-adjacent adhesion contexts.
Reason: Accept as a core localization. CASS4/HEPL is described as a Cas-family docking scaffold with focal-adhesion localization, and the GOA experimental and family-based annotations consistently place it in cytoplasm/cytoskeleton/focal-adhesion contexts.
GO:0005737 cytoplasm
IMP
PMID:27677288
Overexpression of CASS4 promotes invasion in non-small cell ... 		ACCEPT
Summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, and membrane-adjacent adhesion contexts.
Reason: Accept as a core localization. CASS4/HEPL is described as a Cas-family docking scaffold with focal-adhesion localization, and the GOA experimental and family-based annotations consistently place it in cytoplasm/cytoskeleton/focal-adhesion contexts.
GO:0030335 positive regulation of cell migration
IMP
PMID:27677288
Overexpression of CASS4 promotes invasion in non-small cell ... 		ACCEPT
Summary: CASS4/HEPL supports migration and invasion-related adhesion signaling in Cas-family and NSCLC evidence.
Reason: Accept as part of the core phenotype of Cas-family adhesion signaling. The original HEPL paper and NSCLC studies connect CASS4/HEPL with cell spreading, migration, invasion, and focal-adhesion signaling.
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
IMP
PMID:27677288
Overexpression of CASS4 promotes invasion in non-small cell ... 		KEEP AS NON CORE
Summary: CASS4 can activate AKT signaling in an NSCLC invasion model, but this is a downstream disease-context pathway rather than the defining Cas scaffold function.
Reason: Keep as non-core. The cached abstract reports CASS4-dependent AKT Ser473 phosphorylation and invasion changes in NSCLC cells, supporting the annotation in that context. However, AKT activation is downstream and context-specific relative to the central focal-adhesion/FAK scaffold function.
GO:0030335 positive regulation of cell migration
IMP
PMID:18256281
A novel Cas family member, HEPL, regulates FAK and cell spre... 		ACCEPT
Summary: CASS4/HEPL supports migration and invasion-related adhesion signaling in Cas-family and NSCLC evidence.
Reason: Accept as part of the core phenotype of Cas-family adhesion signaling. The original HEPL paper and NSCLC studies connect CASS4/HEPL with cell spreading, migration, invasion, and focal-adhesion signaling.
GO:0061098 positive regulation of protein tyrosine kinase activity
IDA
PMID:18256281
A novel Cas family member, HEPL, regulates FAK and cell spre... 		ACCEPT
Summary: CASS4/HEPL is a Cas-family focal-adhesion docking scaffold that regulates FAK/protein-tyrosine-kinase signaling, focal adhesion integrity, substrate-dependent cell spreading, and migration.
Reason: Accept as part of the core CASS4 function. The original HEPL paper directly places Cas proteins in integrin-dependent focal-adhesion signaling and reports that HEPL localizes to focal adhesions while regulating FAK activity, focal adhesion integrity, and cell spreading. The PANTHER Cas scaffolding family placement and the remaining experimental annotations are consistent with this focal-adhesion scaffold role.
GO:1900026 positive regulation of substrate adhesion-dependent cell spreading
IMP
PMID:18256281
A novel Cas family member, HEPL, regulates FAK and cell spre... 		ACCEPT
Summary: CASS4/HEPL is a Cas-family focal-adhesion docking scaffold that regulates FAK/protein-tyrosine-kinase signaling, focal adhesion integrity, substrate-dependent cell spreading, and migration.
Reason: Accept as part of the core CASS4 function. The original HEPL paper directly places Cas proteins in integrin-dependent focal-adhesion signaling and reports that HEPL localizes to focal adhesions while regulating FAK activity, focal adhesion integrity, and cell spreading. The PANTHER Cas scaffolding family placement and the remaining experimental annotations are consistent with this focal-adhesion scaffold role.
GO:1990782 protein tyrosine kinase binding
IPI
PMID:18256281
A novel Cas family member, HEPL, regulates FAK and cell spre... 		ACCEPT
Summary: CASS4/HEPL is a Cas-family focal-adhesion docking scaffold that regulates FAK/protein-tyrosine-kinase signaling, focal adhesion integrity, substrate-dependent cell spreading, and migration.
Reason: Accept as part of the core CASS4 function. The original HEPL paper directly places Cas proteins in integrin-dependent focal-adhesion signaling and reports that HEPL localizes to focal adhesions while regulating FAK activity, focal adhesion integrity, and cell spreading. The PANTHER Cas scaffolding family placement and the remaining experimental annotations are consistent with this focal-adhesion scaffold role.
GO:0005925 focal adhesion
IDA
PMID:18256281
A novel Cas family member, HEPL, regulates FAK and cell spre... 		ACCEPT
Summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, and membrane-adjacent adhesion contexts.
Reason: Accept as a core localization. CASS4/HEPL is described as a Cas-family docking scaffold with focal-adhesion localization, and the GOA experimental and family-based annotations consistently place it in cytoplasm/cytoskeleton/focal-adhesion contexts.

Core Functions

Cas-family focal-adhesion docking/scaffold function linking integrin-dependent adhesion sites to FAK/protein tyrosine kinase signaling, focal adhesion integrity, substrate-dependent cell spreading, and migration.

Molecular Function:
protein tyrosine kinase binding
Directly Involved In:
integrin-mediated signaling pathway positive regulation of protein tyrosine kinase activity positive regulation of substrate adhesion-dependent cell spreading cell migration
Cellular Locations:
focal adhesion cytoplasm cytoskeleton
Supporting Evidence:

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:18256281
A novel Cas family member, HEPL, regulates FAK and cell spreading.
PMID:23001926
Overexpression and cytoplasmic accumulation of Hepl is associated with clinicopathological parameters and poor prognosis in non-small cell lung cancer.
PMID:27677288
Overexpression of CASS4 promotes invasion in non-small cell lung cancer by activating the AKT signaling pathway and inhibiting E-cadherin expression.

Suggested Questions for Experts

Q: Does Alzheimer-associated CASS4 biology act through microglial, vascular, synaptic, or extracellular-matrix adhesion and migration states rather than through cancer-derived invasion mechanisms?

Q: Which CASS4-dependent FAK, PI3K/AKT, and cytoskeletal outputs are reproducible in brain-relevant human cell types?

Q: Which interaction partners recruit endogenous CASS4 to focal adhesions or related adhesion structures in neural and immune cells?

Suggested Experiments

Experiment: Perturb CASS4 in human iPSC-derived microglia, endothelial cells, astrocytes, and neuronal co-cultures, then quantify FAK phosphorylation, focal-adhesion dynamics, cell spreading, migration, phagocytosis, and extracellular-matrix responses under amyloid or inflammatory stress.

Hypothesis: CASS4 Alzheimer relevance depends on Cas-family focal-adhesion signaling in brain-relevant adhesion and migration states.

Type: cell-type-specific focal-adhesion signaling assay

Experiment: Rescue CASS4 loss with wild-type and SH3/domain-mutant constructs in adhesion-dependent cells and measure PTK2/FAK binding, FAK activation, AKT phosphorylation, focal-adhesion integrity, and substrate-dependent cell spreading.

Hypothesis: CASS4 scaffolding regulates FAK and PI3K/AKT outputs through focal-adhesion recruitment rather than a canonical receptor tyrosine kinase pathway.

Type: structure-function rescue assay

📚 Additional Documentation

Notes

(CASS4-notes.md)

CASS4 notes

Automated deep research was attempted with just deep-research-falcon human CASS4 --fallback perplexity-lite, but the run timed out before producing a deep-research file. This review therefore uses cached GOA publications, the UniProt record, and the PANTHER family fetch.

CASS4 encodes Cas scaffolding protein family member 4, also called HEPL. UniProt describes CASS4 as a docking protein involved in tyrosine kinase-based signaling related to cell adhesion and spreading, regulating PTK2/FAK1 activity, focal adhesion integrity, and cell spreading. The local PANTHER fetch places CASS4 in PTHR10654:SF19, the CAS scaffolding protein family member 4 subfamily.

The core CASS4 evidence comes from the original HEPL paper. Although only the abstract is cached, it directly supports the family context and focal-adhesion/FAK/spreading function: "Cas proteins mediate integrin-dependent signals at focal adhesions, regulating cell invasion and survival" and "HEPL maintains Cas family function in localization to focal adhesions, as well as regulation of FAK activity, focal adhesion integrity, and cell spreading" [PMID:18256281 "Cas proteins mediate integrin-dependent signals at focal adhesions, regulating cell invasion and survival"; PMID:18256281 "HEPL maintains Cas family function in localization to focal adhesions, as well as regulation of FAK activity, focal adhesion integrity, and cell spreading"].

The NSCLC expression paper supports cytoplasmic accumulation and a disease-context migration/metastasis association. The abstract says Hepl is the fourth CAS family member, varies in migration effects by cell type, and is overexpressed/cytoplasmically accumulated in NSCLC [PMID:23001926 "Hepl, first described in 2008, is the fourth member of the Crk-associated substrate (CAS) family"; PMID:23001926 "Compared to other CAS proteins, Hepl has a varying effect on cell migration in different cell types"; PMID:23001926 "cytoplasmic accumulation of Hepl was observed in a high metastatic potential lung cancer cell lines"].

The later NSCLC paper supports positive regulation of invasion/migration and AKT signaling in a cancer-specific context. Its abstract reports that CASS4 overexpression enhanced invasion, CASS4 depletion inhibited invasion, and CASS4 facilitated AKT phosphorylation [PMID:27677288 "CASS4 overexpression inhibited E-cadherin expression and enhanced invasion in NSCLC cell line"; PMID:27677288 "CASS4 depletion upregulated E-cadherin expression and inhibited invasion"; PMID:27677288 "CASS4 facilitated AKT (Ser473) phosphorylation"].

For curation, accept focal adhesion, cytoplasm/cytoskeleton, protein tyrosine kinase binding, FAK activity regulation, spreading, and migration annotations as the central Cas-scaffold biology. Keep AKT-pathway activation as non-core because it is a downstream NSCLC invasion phenotype. Modify the broad cell surface receptor protein tyrosine kinase signaling pathway IBA to integrin-mediated signaling pathway, which better matches the Cas/focal-adhesion evidence and avoids implying a canonical receptor tyrosine kinase pathway.

2026-06-20 second-pass audit

The second-pass audit confirmed the existing CASS4 review and manual reference metadata. No annotation action changes were needed: CASS4 remains curated as a CAS-family focal-adhesion scaffold regulating FAK/integrin-linked spreading and migration, with AKT-pathway and cancer-invasion annotations retained as downstream context rather than the core molecular role.

📄 View Raw YAML

 
id: Q9NQ75
gene_symbol: CASS4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'CASS4 encodes Cas scaffolding protein family member 4, also called HEPL,
  a Crk-associated substrate family docking protein that acts at focal adhesions and
  cytoskeletal adhesion sites. CASS4 links integrin-dependent adhesion sites to focal
  adhesion kinase/protein tyrosine kinase signaling, helping regulate focal adhesion
  integrity, substrate-dependent cell spreading, and cell migration. Cancer-cell studies
  additionally support context-specific roles in invasion and AKT pathway activation,
  while the Alzheimer-disease-relevant cellular mechanism remains unresolved.'
alternative_products:
- name: '1'
  id: Q9NQ75-1
- name: '2'
  id: Q9NQ75-2
  sequence_note: VSP_003807
- name: '3'
  id: Q9NQ75-3
  sequence_note: VSP_003806
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, 
      and membrane-adjacent adhesion contexts.
    action: ACCEPT
    reason: Accept as a core localization. CASS4/HEPL is described as a 
      Cas-family docking scaffold with focal-adhesion localization, and the GOA 
      experimental and family-based annotations consistently place it in 
      cytoplasm/cytoskeleton/focal-adhesion contexts.
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:0016477
    label: cell migration
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: CASS4/HEPL supports migration and invasion-related adhesion 
      signaling in Cas-family and NSCLC evidence.
    action: ACCEPT
    reason: Accept as part of the core phenotype of Cas-family adhesion 
      signaling. The original HEPL paper and NSCLC studies connect CASS4/HEPL 
      with cell spreading, migration, invasion, and focal-adhesion signaling.
    additional_reference_ids:
    - PMID:18256281
    - PMID:23001926
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: colocalizes_with
  review:
    summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, 
      and membrane-adjacent adhesion contexts.
    action: ACCEPT
    reason: Accept as a core localization. CASS4/HEPL is described as a 
      Cas-family docking scaffold with focal-adhesion localization, and the GOA 
      experimental and family-based annotations consistently place it in 
      cytoplasm/cytoskeleton/focal-adhesion contexts.
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:0007169
    label: cell surface receptor protein tyrosine kinase signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: The broad receptor-tyrosine-kinase signaling IBA captures 
      adhesion-associated tyrosine kinase signaling but is too broad and points 
      to the wrong signaling branch.
    action: MODIFY
    reason: Modify to integrin-mediated signaling pathway. The direct HEPL 
      evidence describes integrin-dependent signals at focal adhesions and 
      regulation of FAK activity, not canonical signaling through a cell-surface
      receptor protein tyrosine kinase. Integrin-mediated signaling better 
      captures the Cas-family focal-adhesion context.
    proposed_replacement_terms:
    - id: GO:0007229
      label: integrin-mediated signaling pathway
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, 
      and membrane-adjacent adhesion contexts.
    action: ACCEPT
    reason: Accept as a core localization. CASS4/HEPL is described as a 
      Cas-family docking scaffold with focal-adhesion localization, and the GOA 
      experimental and family-based annotations consistently place it in 
      cytoplasm/cytoskeleton/focal-adhesion contexts.
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, 
      and membrane-adjacent adhesion contexts.
    action: ACCEPT
    reason: Accept as a core localization. CASS4/HEPL is described as a 
      Cas-family docking scaffold with focal-adhesion localization, and the GOA 
      experimental and family-based annotations consistently place it in 
      cytoplasm/cytoskeleton/focal-adhesion contexts.
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23001926
  qualifier: located_in
  review:
    summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, 
      and membrane-adjacent adhesion contexts.
    action: ACCEPT
    reason: Accept as a core localization. CASS4/HEPL is described as a 
      Cas-family docking scaffold with focal-adhesion localization, and the GOA 
      experimental and family-based annotations consistently place it in 
      cytoplasm/cytoskeleton/focal-adhesion contexts.
    additional_reference_ids:
    - PMID:23001926
    - PMID:18256281
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IMP
  original_reference_id: PMID:27677288
  qualifier: located_in
  review:
    summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, 
      and membrane-adjacent adhesion contexts.
    action: ACCEPT
    reason: Accept as a core localization. CASS4/HEPL is described as a 
      Cas-family docking scaffold with focal-adhesion localization, and the GOA 
      experimental and family-based annotations consistently place it in 
      cytoplasm/cytoskeleton/focal-adhesion contexts.
    additional_reference_ids:
    - PMID:27677288
    - PMID:18256281
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IMP
  original_reference_id: PMID:27677288
  qualifier: involved_in
  review:
    summary: CASS4/HEPL supports migration and invasion-related adhesion 
      signaling in Cas-family and NSCLC evidence.
    action: ACCEPT
    reason: Accept as part of the core phenotype of Cas-family adhesion 
      signaling. The original HEPL paper and NSCLC studies connect CASS4/HEPL 
      with cell spreading, migration, invasion, and focal-adhesion signaling.
    additional_reference_ids:
    - PMID:18256281
    - PMID:27677288
- term:
    id: GO:0051897
    label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B
      signal transduction
  evidence_type: IMP
  original_reference_id: PMID:27677288
  qualifier: involved_in
  review:
    summary: CASS4 can activate AKT signaling in an NSCLC invasion model, but 
      this is a downstream disease-context pathway rather than the defining Cas 
      scaffold function.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core. The cached abstract reports CASS4-dependent AKT 
      Ser473 phosphorylation and invasion changes in NSCLC cells, supporting the
      annotation in that context. However, AKT activation is downstream and 
      context-specific relative to the central focal-adhesion/FAK scaffold 
      function.
    additional_reference_ids:
    - PMID:27677288
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IMP
  original_reference_id: PMID:18256281
  qualifier: involved_in
  review:
    summary: CASS4/HEPL supports migration and invasion-related adhesion 
      signaling in Cas-family and NSCLC evidence.
    action: ACCEPT
    reason: Accept as part of the core phenotype of Cas-family adhesion 
      signaling. The original HEPL paper and NSCLC studies connect CASS4/HEPL 
      with cell spreading, migration, invasion, and focal-adhesion signaling.
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:0061098
    label: positive regulation of protein tyrosine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:18256281
  qualifier: involved_in
  review:
    summary: CASS4/HEPL is a Cas-family focal-adhesion docking scaffold that 
      regulates FAK/protein-tyrosine-kinase signaling, focal adhesion integrity,
      substrate-dependent cell spreading, and migration.
    action: ACCEPT
    reason: Accept as part of the core CASS4 function. The original HEPL paper 
      directly places Cas proteins in integrin-dependent focal-adhesion 
      signaling and reports that HEPL localizes to focal adhesions while 
      regulating FAK activity, focal adhesion integrity, and cell spreading. The
      PANTHER Cas scaffolding family placement and the remaining experimental 
      annotations are consistent with this focal-adhesion scaffold role.
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:1900026
    label: positive regulation of substrate adhesion-dependent cell spreading
  evidence_type: IMP
  original_reference_id: PMID:18256281
  qualifier: involved_in
  review:
    summary: CASS4/HEPL is a Cas-family focal-adhesion docking scaffold that 
      regulates FAK/protein-tyrosine-kinase signaling, focal adhesion integrity,
      substrate-dependent cell spreading, and migration.
    action: ACCEPT
    reason: Accept as part of the core CASS4 function. The original HEPL paper 
      directly places Cas proteins in integrin-dependent focal-adhesion 
      signaling and reports that HEPL localizes to focal adhesions while 
      regulating FAK activity, focal adhesion integrity, and cell spreading. The
      PANTHER Cas scaffolding family placement and the remaining experimental 
      annotations are consistent with this focal-adhesion scaffold role.
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:1990782
    label: protein tyrosine kinase binding
  evidence_type: IPI
  original_reference_id: PMID:18256281
  qualifier: enables
  review:
    summary: CASS4/HEPL is a Cas-family focal-adhesion docking scaffold that 
      regulates FAK/protein-tyrosine-kinase signaling, focal adhesion integrity,
      substrate-dependent cell spreading, and migration.
    action: ACCEPT
    reason: Accept as part of the core CASS4 function. The original HEPL paper 
      directly places Cas proteins in integrin-dependent focal-adhesion 
      signaling and reports that HEPL localizes to focal adhesions while 
      regulating FAK activity, focal adhesion integrity, and cell spreading. The
      PANTHER Cas scaffolding family placement and the remaining experimental 
      annotations are consistent with this focal-adhesion scaffold role.
    additional_reference_ids:
    - PMID:18256281
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IDA
  original_reference_id: PMID:18256281
  qualifier: located_in
  review:
    summary: CASS4/HEPL localizes to cytoplasmic, cytoskeletal, focal-adhesion, 
      and membrane-adjacent adhesion contexts.
    action: ACCEPT
    reason: Accept as a core localization. CASS4/HEPL is described as a 
      Cas-family docking scaffold with focal-adhesion localization, and the GOA 
      experimental and family-based annotations consistently place it in 
      cytoplasm/cytoskeleton/focal-adhesion contexts.
    additional_reference_ids:
    - PMID:18256281
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:18256281
  title: A novel Cas family member, HEPL, regulates FAK and cell spreading.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract directly supports the Cas-family context, 
      focal-adhesion localization, FAK regulation, focal-adhesion integrity, and
      cell-spreading function of HEPL/CASS4.
- id: PMID:23001926
  title: Overexpression and cytoplasmic accumulation of Hepl is associated with 
    clinicopathological parameters and poor prognosis in non-small cell lung 
    cancer.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports CASS4/HEPL as a CAS-family member 
      with cytoplasmic accumulation and migration/metastasis association in 
      NSCLC, but it is disease-context evidence.
- id: PMID:27677288
  title: Overexpression of CASS4 promotes invasion in non-small cell lung cancer
    by activating the AKT signaling pathway and inhibiting E-cadherin 
    expression.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports CASS4-dependent NSCLC invasion and 
      AKT phosphorylation, useful for non-core downstream pathway and migration 
      annotations.
core_functions:
- description: Cas-family focal-adhesion docking/scaffold function linking 
    integrin-dependent adhesion sites to FAK/protein tyrosine kinase signaling, 
    focal adhesion integrity, substrate-dependent cell spreading, and migration.
  supported_by:
  - reference_id: PMID:18256281
    supporting_text: integrin-dependent signals at focal adhesions
  - reference_id: PMID:18256281
    supporting_text: regulation of FAK
  - reference_id: PMID:18256281
    supporting_text: focal adhesion integrity, and cell spreading
  molecular_function:
    id: GO:1990782
    label: protein tyrosine kinase binding
  directly_involved_in:
  - id: GO:0007229
    label: integrin-mediated signaling pathway
  - id: GO:0061098
    label: positive regulation of protein tyrosine kinase activity
  - id: GO:1900026
    label: positive regulation of substrate adhesion-dependent cell spreading
  - id: GO:0016477
    label: cell migration
  locations:
  - id: GO:0005925
    label: focal adhesion
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005856
    label: cytoskeleton
proposed_new_terms: []
suggested_questions:
- question: Does Alzheimer-associated CASS4 biology act through microglial, 
    vascular, synaptic, or extracellular-matrix adhesion and migration states 
    rather than through cancer-derived invasion mechanisms?
- question: Which CASS4-dependent FAK, PI3K/AKT, and cytoskeletal outputs are 
    reproducible in brain-relevant human cell types?
- question: Which interaction partners recruit endogenous CASS4 to focal 
    adhesions or related adhesion structures in neural and immune cells?
suggested_experiments:
- hypothesis: CASS4 Alzheimer relevance depends on Cas-family focal-adhesion 
    signaling in brain-relevant adhesion and migration states.
  description: Perturb CASS4 in human iPSC-derived microglia, endothelial cells,
    astrocytes, and neuronal co-cultures, then quantify FAK phosphorylation, 
    focal-adhesion dynamics, cell spreading, migration, phagocytosis, and 
    extracellular-matrix responses under amyloid or inflammatory stress.
  experiment_type: cell-type-specific focal-adhesion signaling assay
- hypothesis: CASS4 scaffolding regulates FAK and PI3K/AKT outputs through 
    focal-adhesion recruitment rather than a canonical receptor tyrosine kinase 
    pathway.
  description: Rescue CASS4 loss with wild-type and SH3/domain-mutant constructs
    in adhesion-dependent cells and measure PTK2/FAK binding, FAK activation, 
    AKT phosphorylation, focal-adhesion integrity, and substrate-dependent cell 
    spreading.
  experiment_type: structure-function rescue assay