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.
| 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. Proposed replacements: integrin-mediated signaling pathway |
| 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. |
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Download this section (compressed HTML)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?
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
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