NEDD9 (HEF1, CAS-L, CASS2) is a member of the Cas (Crk-associated substrate) family of multidomain docking proteins, with an N-terminal SH3 domain, a substrate domain carrying many YxxP tyrosine motifs, a serine-rich four-helix bundle and a conserved C-terminal FAT-like domain that binds NSP proteins (BCAR3, SH2D3C). Full-length NEDD9 localizes mainly to focal adhesions and the cell periphery, where it binds FAK and is tyrosine-phosphorylated by FAK, Src-family and Abl kinases after integrin, TCR/BCR or chemokine stimulation, recruiting SH2-containing partners to promote adhesion, spreading and migration of fibroblasts, lymphocytes and tumor cells. NEDD9 levels are cell-cycle regulated and controlled by SMAD3/ITCH-mediated ubiquitination and caspase cleavage; at mitosis a pool relocalizes to centrosomes and the spindle, where NEDD9 binds and activates Aurora A kinase and influences RhoA activation via ECT2. In ciliated cells, NEDD9-dependent activation of Aurora A at the basal body triggers HDAC6-mediated axonemal deacetylation and primary cilium disassembly. NEDD9 is overexpressed in several metastatic cancers.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000922 spindle pole | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping. Reason: NEDD9 (notably the p55 fragment) relocalizes to the mitotic spindle/spindle asters and centrosomes in mitosis, where it contributes to AURKA activation and RhoA regulation; a real but secondary location. Supporting Evidence: PMID:16184168 Although HEF1 has a well-defined role in integrin-dependent attachment signalling at focal adhesions, it relocalizes to the spindle asters at mitosis |
| GO:0000922 spindle pole | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer. Reason: NEDD9 (notably the p55 fragment) relocalizes to the mitotic spindle/spindle asters and centrosomes in mitosis, where it contributes to AURKA activation and RhoA regulation; a real but secondary location. Supporting Evidence: PMID:16184168 Although HEF1 has a well-defined role in integrin-dependent attachment signalling at focal adhesions, it relocalizes to the spindle asters at mitosis |
| GO:0001772 immunological synapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse: NEDD9 at the T-cell immunological synapse. Reason: Lymphocyte-specific context of the general adhesion-signalling scaffold role. |
| GO:0005515 protein binding | IPI PMID:11827972 MICAL, a novel CasL interacting molecule, associates with vi... | REMOVE | Summary: MICAL1 binds the NEDD9/CasL SH3 domain via its PPKPP motif. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. Supporting Evidence: PMID:11827972 MICAL is a cytoplasmic protein and colocalizes with CasL at the perinuclear area |
| GO:0005515 protein binding | IPI PMID:15051726 Atrophin-1-interacting protein 4/human Itch is a ubiquitin E... | REMOVE | Summary: NEDD9 forms a complex with SMAD3 and the E3 ligase ITCH/AIP4, which ubiquitinates NEDD9 for degradation; NEDD9 is the substrate. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. Supporting Evidence: PMID:15051726 AIP4 forms a complex with both Smad3 and HEF1 through its WW domains |
| GO:0005515 protein binding | IPI PMID:16394104 Deregulation of HEF1 impairs M-phase progression by disrupti... | REMOVE | Summary: NEDD9 associates with the RhoGEF ECT2 in mitosis. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. Supporting Evidence: PMID:16394104 HEF1 associates with the RhoA-GTP exchange factor ECT2 |
| GO:0005515 protein binding | IPI PMID:19103205 Structural insights into the association between BCAR3 and C... | REMOVE | Summary: The NEDD9 C-terminal four-helix bundle binds the Cdc25-like domain of BCAR3/NSP family proteins (structural study). The binding is well characterised but 'protein binding' adds nothing. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. Supporting Evidence: PMID:19103205 HEF1 binds very tightly to a site on BCAR3 that is remote from the putative guanosine triphosphatase binding site of the GEF domain |
| GO:0005515 protein binding | IPI PMID:19275884 SHP-2 inhibits tyrosine phosphorylation of Cas-L and regulat... | MODIFY | Summary: SHP-2 (PTPN11) binds tyrosine-phosphorylated Cas-L via its SH2 domains and dephosphorylates it. Reason: 'Protein binding' is uninformative; the cited evidence supports a more specific binding/adaptor function consistent with NEDD9's role as a Cas-family docking protein. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:19275884 SHP-2 inhibits tyrosine phosphorylation of Cas-L, and associates with Cas-L to form a complex in a tyrosine phosphorylation-dependent manner |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: High-throughput yeast two-hybrid interactome (TRIM27, NAB2, BANP). Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: High-throughput yeast two-hybrid interactome (TRIM27, NAB2, BANP). Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: High-throughput yeast two-hybrid interactome (TRIM27, NAB2, BANP). Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:22810897 Abl family kinases modulate T cell-mediated inflammation and... | MODIFY | Summary: Abl family kinases bind and tyrosine-phosphorylate HEF1 downstream of chemokine receptors. Reason: 'Protein binding' is uninformative; the cited evidence supports a more specific binding/adaptor function consistent with NEDD9's role as a Cas-family docking protein. Proposed replacements: protein tyrosine kinase binding Supporting Evidence: PMID:22810897 mediated the chemokine-induced tyrosine phosphorylation of human enhancer of filamentation 1 (HEF1), an adaptor protein that is required for the activity of the guanosine triphosphatase Rap1 |
| GO:0005515 protein binding | IPI PMID:24574519 NEDD9 regulates actin dynamics through cortactin deacetylati... | MODIFY | Summary: NEDD9 binds cortactin (CTTN) and AURKA and is required to assemble a NEDD9-AURKA-CTTN complex that couples AURKA/HDAC6 to cortactin deacetylation (UniProt: NEDD9 acts as the scaffold required for complex formation). Reason: 'Protein binding' is uninformative; the cited evidence supports a more specific binding/adaptor function consistent with NEDD9's role as a Cas-family docking protein. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:24574519 NEDD9 binds to and regulates acetylation of CTTN in an Aurora A kinase (AURKA)/HDAC6-dependent manner |
| GO:0005515 protein binding | IPI PMID:24574519 NEDD9 regulates actin dynamics through cortactin deacetylati... | MODIFY | Summary: NEDD9 binds cortactin (CTTN) and AURKA and is required to assemble a NEDD9-AURKA-CTTN complex that couples AURKA/HDAC6 to cortactin deacetylation (UniProt: NEDD9 acts as the scaffold required for complex formation). Reason: 'Protein binding' is uninformative; the cited evidence supports a more specific binding/adaptor function consistent with NEDD9's role as a Cas-family docking protein. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:24574519 NEDD9 binds to and regulates acetylation of CTTN in an Aurora A kinase (AURKA)/HDAC6-dependent manner |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid map (HuRI precursor) listing BCAR3, TRIM27, NFKBIA, REL, TRIP6, NAB2, RFX6, BANP, RBPMS, PRR20C. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex AP-MS interaction with BCAR3. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:29191835 Phosphorylation of human enhancer filamentation 1 (HEF1) sti... | REMOVE | Summary: CK1delta-phosphorylated HEF1 Ser780/Thr804 is docked by the PLK1 polo-box domain, which promotes HEF1 transport to focal adhesions. NEDD9 is the docked phospho-ligand; the functional content belongs to PLK1/CK1delta. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. Supporting Evidence: PMID:29191835 CK1Ξ΄ phosphorylates HEF1 at Ser-780 and Thr-804 residues, which allows non-mitotic Plk1 to dock to one of the resulting two phosphoepitopes |
| GO:0005515 protein binding | IPI PMID:29899023 NEDD9 targets COL3A1 to promote endothelial fibrosis and pul... | REMOVE | Summary: NEDD9 interacts with SMAD3 (impaired by Cys18 oxidation) and NKX2-5 in pulmonary artery endothelial cells. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. Supporting Evidence: PMID:29899023 oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro |
| GO:0005515 protein binding | IPI PMID:29899023 NEDD9 targets COL3A1 to promote endothelial fibrosis and pul... | REMOVE | Summary: NEDD9 interacts with SMAD3 (impaired by Cys18 oxidation) and NKX2-5 in pulmonary artery endothelial cells. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. Supporting Evidence: PMID:29899023 oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex 3.0 AP-MS interaction with BCAR3. Reason: Generic 'protein binding' does not convey NEDD9 function. The interaction is real (or, for high-throughput screens, reported) but carries no specific molecular-function information; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:9360983 Tyrosine phosphorylation of Crk-associated substrates by foc... | MODIFY | Summary: FYN binds Cas-L at the FAK-phosphorylated YDYVHL motif; Src-family kinases then phosphorylate the substrate domain. Reason: 'Protein binding' is uninformative; the cited evidence supports a more specific binding/adaptor function consistent with NEDD9's role as a Cas-family docking protein. Proposed replacements: protein tyrosine kinase binding Supporting Evidence: PMID:9360983 the phosphorylated YDYVHL sequence is a binding site for Src family protein-tyrosine kinases |
| GO:0005634 nucleus | EXP PMID:9584194 Cell cycle-regulated processing of HEF1 to multiple protein ... | KEEP AS NON CORE | Summary: HEF1 forms differentially targeted, including nucleus. Reason: A nuclear pool of NEDD9 (and the caspase-generated p55 fragment) is reported, but nuclear function is poorly defined relative to its focal-adhesion scaffold role. Supporting Evidence: PMID:9584194 While p105(HEF1) and p115(HEF1) are predominantly cytoplasmic and localize to focal adhesions, p55(HEF1) unexpectedly is shown to associate with the mitotic spindle |
| GO:0005634 nucleus | IDA PMID:29899023 NEDD9 targets COL3A1 to promote endothelial fibrosis and pul... | KEEP AS NON CORE | Summary: NEDD9-NKX2-5 complex in endothelial cells. Reason: A nuclear pool of NEDD9 (and the caspase-generated p55 fragment) is reported, but nuclear function is poorly defined relative to its focal-adhesion scaffold role. Supporting Evidence: PMID:29899023 oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping. Reason: A nuclear pool of NEDD9 (and the caspase-generated p55 fragment) is reported, but nuclear function is poorly defined relative to its focal-adhesion scaffold role. |
| GO:0005634 nucleus | TAS PMID:8668148 Human enhancer of filamentation 1, a novel p130cas-like dock... | KEEP AS NON CORE | Summary: HEF1 at cell periphery and nucleus. Reason: A nuclear pool of NEDD9 (and the caspase-generated p55 fragment) is reported, but nuclear function is poorly defined relative to its focal-adhesion scaffold role. Supporting Evidence: PMID:8668148 HEF1 localizes to both the cell periphery and the cell nucleus |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence: nucleoplasm. Reason: A nuclear pool of NEDD9 (and the caspase-generated p55 fragment) is reported, but nuclear function is poorly defined relative to its focal-adhesion scaffold role. |
| GO:0005737 cytoplasm | EXP PMID:11827972 MICAL, a novel CasL interacting molecule, associates with vi... | ACCEPT | Summary: CasL cytoplasmic/perinuclear localization with MICAL. Reason: NEDD9 is predominantly cytoplasmic (focal adhesions, cell periphery, cortex). Supporting Evidence: PMID:11827972 MICAL is a cytoplasmic protein and colocalizes with CasL at the perinuclear area |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference (Cas family). Reason: NEDD9 is predominantly cytoplasmic (focal adhesions, cell periphery, cortex). Supporting Evidence: PMID:9584194 While p105(HEF1) and p115(HEF1) are predominantly cytoplasmic and localize to focal adhesions, p55(HEF1) unexpectedly is shown to associate with the mitotic spindle |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping. Reason: NEDD9 is predominantly cytoplasmic (focal adhesions, cell periphery, cortex). Supporting Evidence: PMID:9584194 While p105(HEF1) and p115(HEF1) are predominantly cytoplasmic and localize to focal adhesions, p55(HEF1) unexpectedly is shown to associate with the mitotic spindle |
| GO:0005737 cytoplasm | TAS PMID:9584194 Cell cycle-regulated processing of HEF1 to multiple protein ... | ACCEPT | Summary: p105/p115 HEF1 predominantly cytoplasmic. Reason: NEDD9 is predominantly cytoplasmic (focal adhesions, cell periphery, cortex). Supporting Evidence: PMID:9584194 While p105(HEF1) and p115(HEF1) are predominantly cytoplasmic and localize to focal adhesions, p55(HEF1) unexpectedly is shown to associate with the mitotic spindle |
| GO:0005794 Golgi apparatus | EXP PMID:8668148 Human enhancer of filamentation 1, a novel p130cas-like dock... | KEEP AS NON CORE | Summary: Golgi localization reported in the original HEF1 characterization (full text). Reason: The abstract reports differential peripheral/nuclear localization; a Golgi pool is presumably documented in the full text, which was not available. Not contradicted, but peripheral to NEDD9 function. Supporting Evidence: PMID:8668148 HEF1 localizes to both the cell periphery and the cell nucleus |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping. Reason: As above; peripheral. |
| GO:0005819 spindle | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined automated annotation. Reason: NEDD9 (notably the p55 fragment) relocalizes to the mitotic spindle/spindle asters and centrosomes in mitosis, where it contributes to AURKA activation and RhoA regulation; a real but secondary location. Supporting Evidence: PMID:9584194 While p105(HEF1) and p115(HEF1) are predominantly cytoplasmic and localize to focal adhesions, p55(HEF1) unexpectedly is shown to associate with the mitotic spindle |
| GO:0005819 spindle | TAS PMID:9584194 Cell cycle-regulated processing of HEF1 to multiple protein ... | KEEP AS NON CORE | Summary: p55 HEF1 associates with the mitotic spindle. Reason: NEDD9 (notably the p55 fragment) relocalizes to the mitotic spindle/spindle asters and centrosomes in mitosis, where it contributes to AURKA activation and RhoA regulation; a real but secondary location. Supporting Evidence: PMID:9584194 While p105(HEF1) and p115(HEF1) are predominantly cytoplasmic and localize to focal adhesions, p55(HEF1) unexpectedly is shown to associate with the mitotic spindle |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence: cytosol. Reason: NEDD9 is predominantly cytoplasmic (focal adhesions, cell periphery, cortex). |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt location mapping to cytoskeleton. Reason: General; consistent with focal-adhesion/actin-associated and spindle pools. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference: colocalizes with plasma membrane. Reason: Cas proteins are recruited to membrane-proximal adhesion complexes; peripheral descriptor. Supporting Evidence: PMID:8668148 HEF1 localizes to both the cell periphery and the cell nucleus |
| GO:0005925 focal adhesion | IDA PMID:19103205 Structural insights into the association between BCAR3 and C... | ACCEPT | Summary: NEDD9 at focal adhesions (BCAR3/Cas complex study). Reason: NEDD9 full-length p105/p115 forms localize to focal adhesions, its principal site of action in integrin signalling. Supporting Evidence: PMID:9584194 While p105(HEF1) and p115(HEF1) are predominantly cytoplasmic and localize to focal adhesions, p55(HEF1) unexpectedly is shown to associate with the mitotic spindle |
| GO:0005925 focal adhesion | IDA PMID:19275884 SHP-2 inhibits tyrosine phosphorylation of Cas-L and regulat... | ACCEPT | Summary: Cas-L colocalizes with SHP-2 at focal adhesions. Reason: NEDD9 full-length p105/p115 forms localize to focal adhesions, its principal site of action in integrin signalling. Supporting Evidence: PMID:19275884 overexpressed SHP-2 co-localizes with Cas-L at focal adhesions |
| GO:0005925 focal adhesion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping. Reason: NEDD9 full-length p105/p115 forms localize to focal adhesions, its principal site of action in integrin signalling. Supporting Evidence: PMID:9584194 While p105(HEF1) and p115(HEF1) are predominantly cytoplasmic and localize to focal adhesions, p55(HEF1) unexpectedly is shown to associate with the mitotic spindle |
| GO:0005929 cilium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt location mapping to cilium. Reason: NEDD9 acts at the ciliary base (basal body) rather than in the axoneme; 'ciliary basal body' is the informative term. Supporting Evidence: PMID:17604723 interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly |
| GO:0005938 cell cortex | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt location mapping to cell cortex. Reason: Plausible peripheral location. Supporting Evidence: PMID:8668148 HEF1 localizes to both the cell periphery and the cell nucleus |
| GO:0007010 cytoskeleton organization | NAS PMID:11827972 MICAL, a novel CasL interacting molecule, associates with vi... | KEEP AS NON CORE | Summary: CasL linked to intermediate filaments via MICAL. Reason: Statement is speculative (MICAL as a possible cytoskeletal linker) but consistent with NEDD9 roles. Supporting Evidence: PMID:11827972 These results suggest that MICAL may be a cytoskeletal regulator that connects CasL to intermediate filaments |
| GO:0007155 cell adhesion | NAS PMID:9584194 Cell cycle-regulated processing of HEF1 to multiple protein ... | ACCEPT | Summary: Cas family docking proteins coordinate regulation of cell adhesion. Reason: Core process of the Cas-family scaffold. Supporting Evidence: PMID:9584194 HEF1, p130(Cas), and Efs/Sin constitute a family of multidomain docking proteins that have been implicated in coordinating the regulation of cell adhesion |
| GO:0007165 signal transduction | TAS PMID:8668148 Human enhancer of filamentation 1, a novel p130cas-like dock... | ACCEPT | Summary: HEF1 as a docking protein linking extracellular signalling to the cytoskeleton. Reason: Broad but correct. Supporting Evidence: PMID:8668148 We anticipate that HEF1 may prove to be an important linking element between extracellular signalling and regulation of the cytoskeleton |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference: cell surface receptor protein tyrosine kinase signaling. Reason: Cas proteins are tyrosine-kinase substrates/docking scaffolds in receptor and integrin tyrosine-kinase signalling. Supporting Evidence: PMID:9360983 the phosphorylated YDYVHL sequence is a binding site for Src family protein-tyrosine kinases |
| GO:0007229 integrin-mediated signaling pathway | NAS PMID:11827972 MICAL, a novel CasL interacting molecule, associates with vi... | ACCEPT | Summary: CasL is tyrosine-phosphorylated after beta1 integrin stimulation. Reason: Integrin-dependent tyrosine phosphorylation of NEDD9 by FAK/Src and assembly of signalling complexes on its substrate domain is NEDD9's core function. Supporting Evidence: PMID:11827972 It is tyrosine-phosphorylated following beta(1) integrin and/or T cell receptor stimulation PMID:9360983 We show here that p130(Cas) and Cas-L are FAK substrates |
| GO:0007611 learning or memory | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse Nedd9 knockout (hippocampal dendritic spines, spatial learning). Reason: Tissue- or context-specific outcome of NEDD9's adhesion/chemokine signalling scaffold role, transferred from an ortholog; retained as non-core. |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt (by similarity) location mapping to basolateral membrane. Reason: Ortholog-derived; peripheral. |
| GO:0016323 basolateral plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer. Reason: Ortholog-derived; peripheral. |
| GO:0016477 cell migration | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference: cell migration. Reason: NEDD9 is required for mesenchymal migration of tumor cells and for lymphocyte migration. Supporting Evidence: PMID:24574519 knockdown of NEDD9 in highly metastatic tumor cells drastically reduces their migratory capacity due to disruption of actin dynamics at the leading edge |
| GO:0030027 lamellipodium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt location mapping to lamellipodium. Reason: NEDD9 supports lamellipodial protrusion stability at the leading edge. Supporting Evidence: PMID:24574519 NEDD9 deficiency leads to a decrease in the persistence and stability of lamellipodial protrusions |
| GO:0030335 positive regulation of cell migration | IMP PMID:18256281 A novel Cas family member, HEPL, regulates FAK and cell spre... | ACCEPT | Summary: Cas-family knockdown/regulation of spreading and migration (HEPL study including HEF1). Reason: Consistent with extensive evidence that NEDD9 promotes migration. Supporting Evidence: PMID:18256281 Cas proteins mediate integrin-dependent signals at focal adhesions, regulating cell invasion and survival |
| GO:0030336 negative regulation of cell migration | ISS GO_REF:0000024 | UNDECIDED | Summary: Sequence-similarity transfer: negative regulation of cell migration. Reason: Contrasts with the well-supported positive role of NEDD9 in migration; the source ortholog evidence could not be inspected, so this is left undecided. Supporting Evidence: PMID:24574519 knockdown of NEDD9 in highly metastatic tumor cells drastically reduces their migratory capacity due to disruption of actin dynamics at the leading edge |
| GO:0032956 regulation of actin cytoskeleton organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer: regulation of actin cytoskeleton organization. Reason: Supported by NEDD9 control of leading-edge actin dynamics via cortactin. Supporting Evidence: PMID:24574519 knockdown of NEDD9 in highly metastatic tumor cells drastically reduces their migratory capacity due to disruption of actin dynamics at the leading edge |
| GO:0036064 ciliary basal body | IDA PMID:17604723 HEF1-dependent Aurora A activation induces disassembly of th... | ACCEPT | Summary: HEF1/NEDD9 interacts with AURKA at the basal body of cilia. Reason: Direct localization in the founding HEF1-AurA-HDAC6 study; the location of NEDD9's ciliary-disassembly role. Supporting Evidence: PMID:17604723 interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly |
| GO:0045672 positive regulation of osteoclast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse: NEDD9 promotes RANKL-induced osteoclastogenesis. Reason: Tissue- or context-specific outcome of NEDD9's adhesion/chemokine signalling scaffold role, transferred from an ortholog; retained as non-core. |
| GO:0051017 actin filament bundle assembly | NAS PMID:11827972 MICAL, a novel CasL interacting molecule, associates with vi... | MARK AS OVER ANNOTATED | Summary: Actin filament bundle assembly attributed from the MICAL interaction paper. Reason: The paper links CasL to vimentin intermediate filaments via MICAL; it does not show that NEDD9 participates in actin filament bundle assembly. Supporting Evidence: PMID:11827972 These results suggest that MICAL may be a cytoskeletal regulator that connects CasL to intermediate filaments |
| GO:0061098 positive regulation of protein tyrosine kinase activity | IDA PMID:18256281 A novel Cas family member, HEPL, regulates FAK and cell spre... | KEEP AS NON CORE | Summary: Cas proteins regulate FAK activity. Reason: Cas-family docking supports FAK activity at focal adhesions; regulatory rather than core. Supporting Evidence: 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 |
| GO:0061523 cilium disassembly | IMP PMID:17604723 HEF1-dependent Aurora A activation induces disassembly of th... | ACCEPT | Summary: HEF1/NEDD9 depletion blocks serum-induced ciliary resorption; NEDD9 binds and activates AURKA at the basal body, leading to HDAC6 phosphorylation and axonemal deacetylation. Reason: NEDD9 contributes the activator step of the HEF1-AurA-HDAC6 resorption pathway (its activator activity toward AURKA is shown in vitro). A real but non-dominant NEDD9 function relative to integrin/focal-adhesion signalling. Supporting Evidence: PMID:17604723 interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly PMID:17604723 We show that this pathway is both necessary and sufficient for ciliary resorption |
| GO:0072686 mitotic spindle | IDA PMID:16394104 Deregulation of HEF1 impairs M-phase progression by disrupti... | KEEP AS NON CORE | Summary: HEF1 relocalizes to the spindle at mitosis. Reason: NEDD9 (notably the p55 fragment) relocalizes to the mitotic spindle/spindle asters and centrosomes in mitosis, where it contributes to AURKA activation and RhoA regulation; a real but secondary location. Supporting Evidence: PMID:16394104 The focal adhesion-associated signaling protein HEF1 undergoes a striking relocalization to the spindle at mitosis |
| GO:0097021 lymphocyte migration into lymphoid organs | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer: lymphocyte homing defect in Nedd9-deficient mice. Reason: Tissue- or context-specific outcome of NEDD9's adhesion/chemokine signalling scaffold role, transferred from an ortholog; retained as non-core. Supporting Evidence: PMID:17174122 association with its binding partner Crk-associated substrate in lymphocytes (CasL), and Chat-H-mediated CasL serine-threonine phosphorylation were required for T cell migration |
| GO:0140131 positive regulation of lymphocyte chemotaxis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse lymphocyte studies. Reason: Tissue- or context-specific outcome of NEDD9's adhesion/chemokine signalling scaffold role, transferred from an ortholog; retained as non-core. Supporting Evidence: PMID:17174122 association with its binding partner Crk-associated substrate in lymphocytes (CasL), and Chat-H-mediated CasL serine-threonine phosphorylation were required for T cell migration |
| GO:1900026 positive regulation of substrate adhesion-dependent cell spreading | IMP PMID:18256281 A novel Cas family member, HEPL, regulates FAK and cell spre... | KEEP AS NON CORE | Summary: Cas proteins promote substrate adhesion-dependent cell spreading. Reason: Consistent with the adhesion-signalling role. Supporting Evidence: 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 |
| GO:1902952 positive regulation of dendritic spine maintenance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse Nedd9 knockout. Reason: Tissue- or context-specific outcome of NEDD9's adhesion/chemokine signalling scaffold role, transferred from an ortholog; retained as non-core. |
| GO:1903829 positive regulation of protein localization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from ortholog; vague process term. Reason: Tissue- or context-specific outcome of NEDD9's adhesion/chemokine signalling scaffold role, transferred from an ortholog; retained as non-core. |
| GO:1990782 protein tyrosine kinase binding | IPI PMID:18256281 A novel Cas family member, HEPL, regulates FAK and cell spre... | ACCEPT | Summary: Cas-family protein binding to focal adhesion kinase (PTK2) via the N-terminal SH3 domain. Reason: NEDD9 binds FAK through its SH3 domain and is a FAK and Src-family substrate; binding tyrosine kinases is central to its docking-protein function. Supporting Evidence: 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 PMID:8668148 an interaction of the SH3 domain of HEF1 with two discrete proline-rich regions of focal adhesion kinase |
| GO:2000522 positive regulation of immunological synapse formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse T-cell studies. Reason: Tissue- or context-specific outcome of NEDD9's adhesion/chemokine signalling scaffold role, transferred from an ortholog; retained as non-core. Supporting Evidence: PMID:17174122 association with its binding partner Crk-associated substrate in lymphocytes (CasL), and Chat-H-mediated CasL serine-threonine phosphorylation were required for T cell migration |
| GO:0043539 protein serine/threonine kinase activator activity | IDA PMID:16184168 The focal adhesion scaffolding protein HEF1 regulates activa... | NEW | Summary: NEDD9/HEF1 binds Aurora A and its minimal AurA-interacting domain (residues 1-363) activates recombinant AURKA in vitro; HEF1 depletion prevents AURKA activation in cells. Reason: Direct in vitro activation of purified AURKA by a NEDD9 fragment plus loss of activation on depletion supports a kinase activator molecular function. This underlies NEDD9's roles in both mitotic AURKA activation and the basal-body pathway of cilium disassembly. Supporting Evidence: PMID:16184168 We show that HEF1 associates with and controls activation of AurA PMID:16184168 we titrated the GST-HEF1 1-363 minimal AurA-interacting domain versus GST into an in vitro kinase reaction containing recombinant AurA purified from bacteria PMID:16184168 In cells depleted for HEF1, AurA does not become activated, suggesting the association with HEF1 is functionally important |
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Download this section (compressed HTML)Q: Does NEDD9 activate Aurora A at the basal body through the same N-terminal (1-363) interaction surface used at mitotic centrosomes, and is NEDD9 required for cilium disassembly in vivo (e.g. in Nedd9-null tissues) or only in serum-stimulated cultured cells, given partial redundancy with Pitchfork/CIMAP3 and Ca2+/calmodulin?
Q: Should NEDD9's scaffold role be captured by 'protein-macromolecule adaptor activity' or by 'signaling adaptor activity', given that it acts as a phosphotyrosine docking platform in integrin and receptor signalling?
Experiment: Rescue of NEDD9-knockout RPE1 cells with NEDD9 variants lacking the AURKA-binding region versus the FAK-binding SH3 domain, scoring serum-induced cilium resorption and focal-adhesion signalling to separate the two functions.
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