NEDD9

Summary

NEDD9 (neural precursor cell expressed, developmentally down-regulated 9, HGNC:7733) is a protein-coding gene on chromosome 6p24.2, encoding Enhancer of filamentation 1 (Q14511). Scaffolding protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion.

The protein encoded by this gene is a member of the CRK-associated substrates family. Members of this family are adhesion docking molecules that mediate protein-protein interactions for signal transduction pathways. This protein is a focal adhesion protein that acts as a scaffold to regulate signaling complexes important in cell attachment, migration and invasion as well as apoptosis and the cell cycle. This protein has also been reported to have a role in cancer metastasis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4739 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 113 total
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006403

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7733
Approved symbol	NEDD9
Name	neural precursor cell expressed, developmentally down-regulated 9
Location	6p24.2
Locus type	gene with protein product
Status	Approved
Aliases	HEF1, CAS-L, CASS2
Ensembl gene	ENSG00000111859
Ensembl biotype	protein_coding
OMIM	602265
Entrez	4739

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 10 protein_coding, 4 protein_coding_CDS_not_defined, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000379433, ENST00000379446, ENST00000397378, ENST00000448183, ENST00000459670, ENST00000461055, ENST00000468612, ENST00000504387, ENST00000504634, ENST00000505589, ENST00000508546, ENST00000508800, ENST00000512665, ENST00000513989, ENST00000514660, ENST00000620854, ENST00000872132, ENST00000935784, ENST00000955648

RefSeq mRNA: 4 — MANE Select: NM_006403 NM_001142393, NM_001271033, NM_006403, NM_182966

CCDS: CCDS34340, CCDS4520, CCDS47373, CCDS75400

Canonical transcript exons

ENST00000379446 — 7 exons

Exon	Start	End
ENSE00001883582	11183298	11185671
ENSE00003536502	11192345	11192446
ENSE00003543782	11189964	11191205
ENSE00003549051	11188218	11188307
ENSE00003652686	11213281	11213727
ENSE00003662782	11193591	11193692
ENSE00003847936	11232504	11232668

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 98.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.2625 / max 3665.2343, expressed in 1629 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
71717	23.3694	1554
71739	16.4914	456
71738	0.2891	67
71737	0.0444	7
203860	0.0420	6
71736	0.0262	8

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	98.78	gold quality
lower lobe of lung	UBERON:0008949	98.60	gold quality
renal glomerulus	UBERON:0000074	97.80	gold quality
metanephric glomerulus	UBERON:0004736	97.68	gold quality
upper lobe of lung	UBERON:0008948	97.50	gold quality
upper lobe of left lung	UBERON:0008952	97.48	gold quality
lung	UBERON:0002048	97.09	gold quality
cauda epididymis	UBERON:0004360	95.77	gold quality
parotid gland	UBERON:0001831	95.50	gold quality
corpus epididymis	UBERON:0004359	95.40	gold quality
caput epididymis	UBERON:0004358	95.35	gold quality
colonic mucosa	UBERON:0000317	95.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.05	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.97	gold quality
visceral pleura	UBERON:0002401	94.79	gold quality
nephron tubule	UBERON:0001231	94.64	gold quality
omental fat pad	UBERON:0010414	94.58	gold quality
peritoneum	UBERON:0002358	94.56	gold quality
blood	UBERON:0000178	94.41	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.39	gold quality
adipose tissue	UBERON:0001013	94.10	gold quality
tibial nerve	UBERON:0001323	93.91	gold quality
ascending aorta	UBERON:0001496	93.89	gold quality
thoracic aorta	UBERON:0001515	93.88	gold quality
mammary duct	UBERON:0001765	93.53	gold quality
connective tissue	UBERON:0002384	93.49	gold quality
saphenous vein	UBERON:0007318	93.29	gold quality
epithelium of mammary gland	UBERON:0003244	93.27	gold quality
mucosa of urinary bladder	UBERON:0001259	93.22	gold quality
thoracic mammary gland	UBERON:0005200	93.19	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	522.29
E-GEOD-135922	yes	36.18
E-CURD-119	yes	26.19
E-CURD-122	yes	13.96
E-GEOD-130148	yes	7.28
E-MTAB-11268	no	827.42
E-GEOD-124858	no	252.60
E-HCAD-31	no	3.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, GLI3, HIF1A, PAX5, TXK

miRNA regulators (miRDB)

120 targeting NEDD9, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6798-5P	100.00	65.77	699
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• HEF1 expression is regulated by TGF-beta1 and HEF1 phosphorylation is dependent on cell adhesion and Src kinase activity (PMID:12189134)
• Cas-L plays an important role in the pathophysiology of rheumatoid arthritis (PMID:12847683)
• Reults demonstrate the function of atrophin-1-interacting protein 4 as an ubiquitin E3 ligase for human enhancer of filamentation 1. (PMID:15051726)
• NEDD9 is regulated in neuroblastoma cells by all-trans retinoic acid. (PMID:15376324)
• NEDD9 (Cas-L) binds human T-lymphotropic virus type I (HTLV-I) Tax and specifically regulates Tax-NF-kappaB pathway. (PMID:15592516)
• The HEF1 protein overexpression of HEF1 causes an increase in centrosome numbers and multipolar spindles, resembling defects induced by manipulation of the mitotic regulatory kinase Aurora-A (AurA). (PMID:16184168)
• HEF1-promoted processes actively extend from the cell body and resemble neurites both in the manner of process extension and in the distribution of adhesion-associated molecules. (PMID:16344118)
• These results suggest that the adhesion-dependent actin organization regulates proteasomal turnover of HEF1 through the activity of PP2A. (PMID:16352661)
• HEF1 associates with the RhoA-GTP exchange factor ECT2, an orthologue of the Drosophila cytokinetic regulator Pebble, providing a direct means for HEF1 control of RhoA. (PMID:16394104)
• Here, we show that 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, promoting ciliary disassembly. (PMID:17604723)
• HEF1/NEDD9/Cas-L expression and function in signaling relevant to cell attachment, migration, invasion, cell cycle, apoptosis, and oncogenic signal transduction. Review. (PMID:17703068)
• Changes in expression of the scaffold protein HEF1/CAS-L/NEDD9 were found to be a potent prometastatic stimulus in melanoma and other cancers. (PMID:17908996)
• Evidence is presented that variation in NEDD9 is associated wih susceptibility to late-onset Alzheimer and Parkinson diseases. (PMID:18063669)
• Cas-L is one of the targets of inflammatory cytokines and is also modulated by cell adhesion process in neutrophils (PMID:18465784)
• rs760678 SNP of the NEDD9 gene is a weak genetic determinant of Alzheimer’s disease and Parkinson’s disease . (PMID:18579580)
• NEDD9 is directly regulated by atRA through a complex retinoic acid response element (RARE) located in the NEDD9 proximal promoter and consisting of four conserved half-sites separated by 1, 5, and 1 intervening base pairs. (PMID:18585997)
• study presents a pluridisciplinary approach, including small-angle X-ray scattering, that provides first insights into the structure of the complex formed between breast cancer anti-oestrogen resistance 3 (BCAR3) and HEF1 (PMID:19103205)
• These results suggest that SHP-2 regulates tyrosine phosphorylation of Cas-L, hence opposing the effect of kinases, and SHP-2 is a negative regulator of cell migration mediated by Cas-L. (PMID:19275884)
• Overexpression of Cas-L is associated with imatinib-resistant gastrointestinal stromal tumor cells. (PMID:19417561)
• Phosphorylation of HEF1 on serine 369 induces its proteasomal degradation. (PMID:19539609)
• Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. (PMID:19648964)
• B2 RNA seems especially interesting in that it can regulate apoptosis and cell proliferation by modulating HEF1. (PMID:20428794)
• An implication of the NEDD9 allelic variant in late-onset AD, with an independent effect of the apolipoprotein E epsilon4 allele in the risk of developing AD. (PMID:20430066)
• HEF1 is required for VEGF-mediated Head and Neck Squamous Cell Carcinoma cell migration and invasion. (PMID:20498643)
• NEDD9 polymorphism has a possible role in changing the genetic susceptibility to late-onset Alzheimer’s disease in a Han Chinese population. (PMID:21059344)
• Data suggest that HEF1 may represent an attractive candidate for drug targeting in CRC. (PMID:21317929)
• Polymorphism, rs760678, within NEDD9 gene is association with the risk of AD and cognitive performance in Chinese older persons (PMID:21399483)
• Cas proteins do not affect E-cadherin transcription, but rather, BCAR1 and NEDD9 signal through SRC to promote E-cadherin removal from the cell membrane and lysosomal degradation. (PMID:21765937)
• Data reveal that the tumour suppressor PP2A may act via S369 to regulated NEDD9-mediated cell spreading. (PMID:22061964)
• signalling through increased NEDD9 levels requires integrin beta3 signalling, which leads to elevated phosphorylation of integrin beta3 (PMID:22328516)
• NEDD9 is upregulated in lung adenocarcinoma, and overexpression of NEDD9 protein has been strongly correlated with staging and differentiation grade and tumor size in lung adenocarcinoma. (PMID:22447485)
• HEF1 may have a role in carcinogenesis of lung cancer; miRNA be a therapeutic target (PMID:22732573)
• Abl family kinases modulate T cell-mediated inflammation and chemokine-induced migration through the adaptor HEF1 and the GTPase Rap1. (PMID:22810897)
• Results demonstrate the critical role of miR-145 and NEDD9 in regulating glioblastoma invasion and suggest a potential role of NEDD9 as a biomarker for glioma progression. (PMID:22869051)
• The GG genotype of NEDD9 rs760678 polymorphism would be a protective factor for AD in Caucasians but not in Asians.[meta-analysis] (PMID:22963925)
• Overexpression of NEDD9 promoted lung metastasis of an lung cancer cell line in transgenic mice. (PMID:23037767)
• In clinical specimens, elevated expression of NEDD9 was associated with malignant progression and metastasis.CRTC1-NEDD9 signaling axis mediates lung cancer progression caused by LKB1 loss. (PMID:23074285)
• The mean overall survival of NSCLC patients overexpressing NEDD9 (39.10 +/- 6.49 months) was markedly shorter. (PMID:23086683)
• High NEDD9 expression is associated with pancreatic ductal adenocarcinoma. (PMID:23247867)
• The findings indicate that HEF1 promotes EMT and bone invasion in prostate cancer by directly targeted by miR-145, and miR-145 suppresses EMT and invasion, at least in part, through repressing HEF1. (PMID:23355420)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nedd9	ENSDARG00000089878
mus_musculus	Nedd9	ENSMUSG00000021365
rattus_norvegicus	Nedd9	ENSRNOG00000014548
drosophila_melanogaster	p130CAS	FBGN0035101

Paralogs (3): BCAR1 (ENSG00000050820), CASS4 (ENSG00000087589), EFS (ENSG00000100842)

Protein

Protein identifiers

Enhancer of filamentation 1 — Q14511 (reviewed: Q14511)

Alternative names: CRK-associated substrate-related protein, Cas scaffolding protein family member 2, Neural precursor cell expressed developmentally down-regulated protein 9, Renal carcinoma antigen NY-REN-12, p105

All UniProt accessions (6): Q14511, A0A087WUD2, D6RBQ2, D6RDV1, D6REP7, D6RGD7

UniProt curated annotations — full annotation on UniProt →

Function. Scaffolding protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion. As a focal adhesion protein, plays a role in embryonic fibroblast migration. May play an important role in integrin beta-1 or B cell antigen receptor (BCR) mediated signaling in B- and T-cells. Integrin beta-1 stimulation leads to recruitment of various proteins including CRKL and SHPTP2 to the tyrosine phosphorylated form. Promotes adhesion and migration of lymphocytes; as a result required for the correct migration of lymphocytes to the spleen and other secondary lymphoid organs. Plays a role in the organization of T-cell F-actin cortical cytoskeleton and the centralization of T-cell receptor microclusters at the immunological synapse. Negatively regulates cilia outgrowth in polarized cysts. Modulates cilia disassembly via activation of AURKA-mediated phosphorylation of HDAC6 and subsequent deacetylation of alpha-tubulin. Positively regulates RANKL-induced osteoclastogenesis. Required for the maintenance of hippocampal dendritic spines in the dentate gyrus and CA1 regions, thereby involved in spatial learning and memory.

Subunit / interactions. Homodimer. Forms heterodimers with BCAR1/p130cas. Forms complexes with PTK2B/RAFTK, adapter protein CRKL and LYN kinase. Part of a complex composed of NEDD9, AURKA and CTTN; within the complex NEDD9 acts as a scaffold protein and is required for complex formation. Part of a ternary complex composed of SMAD3, ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via N-terminus) with ITCH/AIP4 (via WW domains); the complex mediates ubiquitination and proteasomal degradation of NEDD9/HEF1. Interacts with SMAD3; the interaction promotes NEDD9 ubiquitination and proteasomal degradation. Interacts with ID2. Interacts with CTTN (via N-terminus). Interacts with MICAL. Interacts with TXNL4/DIM1. Interacts with BCAR3 (via Ras-GEF domain). Interacts with SH2D3C isoform 1 and isoform 2. Interacts with ECT2. Interacts with PTPN11/SHP-2 (via SH2 domains); the interaction is enhanced when NEDD9/CAS-L is tyrosine phosphorylated. Interacts (via C-terminus) with PLK1 (via polo box domains). Interacts with NKX2-5. Interacts with SMAD3; the interaction is inhibited by oxidation of NEDD9. Interacts with NEDD9/HEF1; interaction is induced by CXCL12 promotion of ABL-mediated phosphorylation of NEDD9/HEF1. Interacts (via SH3 domain) with PTK2/FAK. Interacts with FYN; in the presence of PTK2. Interacts with INPPL1/SHIP2.

Subcellular location. Cytoplasm. Cell cortex. Nucleus. Golgi apparatus. Cell projection. Lamellipodium. Cell junction. Focal adhesion. Cytoskeleton. Spindle pole. Cilium. Cilium basal body. Basolateral cell membrane Cytoplasm. Spindle.

Tissue specificity. Expressed in B-cells (at protein level). Expressed in the respiratory epithelium of the main bronchi to the bronchioles in the lungs (at protein level). High levels detected in kidney, lung, and placenta. Expressed in lymphocytes.

Post-translational modifications. Cell cycle-regulated processing produces four isoforms: p115, p105, p65, and p55. Isoform p115 arises from p105 phosphorylation and appears later in the cell cycle. Isoform p55 arises from p105 as a result of cleavage at a caspase cleavage-related site and it appears specifically at mitosis. The p65 isoform is poorly detected. Polyubiquitinated by ITCH/AIP4, leading to proteasomal degradation. PTK2/FAK1 phosphorylates the protein at the YDYVHL motif (conserved among all cas proteins) following integrin stimulation. The SRC family kinases (FYN, SRC, LCK and CRK) are recruited to the phosphorylated sites and can phosphorylate other tyrosine residues. Ligation of either integrin beta-1 or B-cell antigen receptor on tonsillar B-cells and B-cell lines promotes tyrosine phosphorylation and both integrin and BCR-mediated tyrosine phosphorylation requires an intact actin network. Phosphorylation is required to recruit NEDD9 to T-cell receptor microclusters at the periphery of newly formed immunological synapses. In fibroblasts transformation with oncogene v-ABL results in an increase in tyrosine phosphorylation. Transiently phosphorylated following CD3 cross-linking and this phosphorylated form binds to CRKL and C3G. A mutant lacking the SH3 domain is phosphorylated upon CD3 cross-linking but not upon integrin beta-1 cross-linking. Tyrosine phosphorylation occurs upon stimulation of the G-protein coupled C1a calcitonin receptor. Calcitonin-stimulated tyrosine phosphorylation is mediated by calcium- and protein kinase C-dependent mechanisms and requires the integrity of the actin cytoskeleton. Phosphorylation at Ser-369 induces proteasomal degradation. Phosphorylated by LYN. Phosphorylation at Ser-780 by CSNK1D or CSNK1E, or phosphorylation of Thr-804 by CSNK1E enhances the interaction of NEDD9 with PLK1.

Domain organisation. Contains a central domain containing multiple potential SH2-binding sites and a C-terminal domain containing a divergent helix-loop-helix (HLH) motif. The SH2-binding sites putatively bind CRKL SH2 domains. The HLH motif confers specific interaction with the HLH protein ID2. It is absolutely required for the induction of pseudohyphal growth in yeast and mediates homodimerization and heterodimerization with BCAR1/p130cas.

Induction. Induced by oxidant stress in pulmonary artery endothelial cells.

Similarity. Belongs to the CAS family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q14511-1	1	yes
Q14511-2	2
Q14511-3	3

RefSeq proteins (4): NP_001135865, NP_001257962, NP_006394, NP_892011 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR014928	Serine_rich_dom	Domain
IPR021901	CAS_C	Domain
IPR035746	NEDD9_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037362	CAS_fam	Family
IPR038319	Serine_rich_sf	Homologous_superfamily

Pfam: PF08824, PF12026, PF14604

UniProt features (58 total): modified residue 13, mutagenesis site 12, region of interest 9, helix 8, compositionally biased region 3, splice variant 3, sequence variant 3, chain 2, turn 2, short sequence motif 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5X3S	X-RAY DIFFRACTION	2.9
2L81	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14511-F1	62.29	0.31

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13): 92, 164, 166, 177, 189, 214, 223, 279, 296, 317, 369, 780, 804

Mutagenesis-validated functional residues (12):

Position	Phenotype
18	abolishes the oxidation-mediated reduction in interaction with smad3.
735	no effect on interaction with plk1.
751	abolishes interaction with bcar3.
754	no effect on interaction with bcar3.
758	no effect on interaction with bcar3.
780	reduces interaction with plk1. reduces protein phosphorylation by csnk1d; when associated with a-804.
780	reduces interaction with plk1. abolishes interaction with plk1; when associated with d-804.
780	abolishes interaction with plk1.
796	no effect on interaction with bcar3.
804	reduces interaction with plk1. reduces protein phosphorylation by csnk1d; when associated with a-780.
804	reduces interaction with plk1. abolishes interaction with plk1; when associated with d-780.
804	no effect on interaction with plk1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 455 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GSE45365_NK_CELL_VS_BCELL_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GCACCTT_MIR18A_MIR18B, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_CELL_CHEMOTAXIS

GO Biological Process (21): cytoskeleton organization (GO:0007010), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), integrin-mediated signaling pathway (GO:0007229), learning or memory (GO:0007611), cell migration (GO:0016477), positive regulation of cell migration (GO:0030335), negative regulation of cell migration (GO:0030336), regulation of actin cytoskeleton organization (GO:0032956), positive regulation of osteoclast differentiation (GO:0045672), actin filament bundle assembly (GO:0051017), cell division (GO:0051301), positive regulation of protein tyrosine kinase activity (GO:0061098), cilium disassembly (GO:0061523), lymphocyte migration into lymphoid organs (GO:0097021), positive regulation of lymphocyte chemotaxis (GO:0140131), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), positive regulation of dendritic spine maintenance (GO:1902952), positive regulation of protein localization (GO:1903829), positive regulation of immunological synapse formation (GO:2000522)

GO Molecular Function (2): protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515)

GO Cellular Component (20): spindle pole (GO:0000922), immunological synapse (GO:0001772), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), spindle (GO:0005819), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell cortex (GO:0005938), basolateral plasma membrane (GO:0016323), lamellipodium (GO:0030027), ciliary basal body (GO:0036064), mitotic spindle (GO:0072686), cytoskeleton (GO:0005856), cilium (GO:0005929), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cellular process	3
cytoplasm	3
cell migration	2
regulation of cell migration	2
spindle	2
intracellular membrane-bounded organelle	2
intracellular membraneless organelle	2
cell periphery	2
plasma membrane bounded cell projection	2
organelle organization	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
cell surface receptor signaling pathway	1
behavior	1
cognition	1
cell motility	1
positive regulation of cell motility	1
negative regulation of cell motility	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
positive regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
cellular component assembly	1
actin filament bundle organization	1
protein tyrosine kinase activity	1
positive regulation of protein kinase activity	1
positive regulation of peptidyl-tyrosine phosphorylation	1
regulation of protein tyrosine kinase activity	1
cilium organization	1
organelle disassembly	1
lymphocyte migration	1
positive regulation of leukocyte chemotaxis	1
lymphocyte chemotaxis	1
regulation of lymphocyte chemotaxis	1

Protein interactions and networks

STRING

2863 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEDD9	MICAL1	Q8TDZ2	998
NEDD9	AURKA	O14965	987
NEDD9	SRC	P12931	929
NEDD9	DOCK3	Q8IZD9	919
NEDD9	PTK2	Q05397	879
NEDD9	HDAC6	Q9UBN7	879
NEDD9	MICAL2	O94851	852
NEDD9	MICAL3	Q7RTP6	829
NEDD9	BCAR3	O75815	779
NEDD9	CRK	P46108	732
NEDD9	SMAD3	P84022	729
NEDD9	CRKL	P46109	726
NEDD9	MICALL1	Q8N3F8	725
NEDD9	BORA	Q6PGQ7	706
NEDD9	MICALL2	Q8IY33	701

IntAct

66 interactions, top by confidence:

A	B	Type	Score
NEDD9	BCAR3	psi-mi:“MI:0915”(physical association)	0.740
BCAR3	NEDD9	psi-mi:“MI:0915”(physical association)	0.740
NEDD9	TRIM27	psi-mi:“MI:0915”(physical association)	0.670
NAB2	NEDD9	psi-mi:“MI:0915”(physical association)	0.670
BANP	NEDD9	psi-mi:“MI:0915”(physical association)	0.670
NEDD9	NAB2	psi-mi:“MI:0915”(physical association)	0.670
TRIM27	NEDD9	psi-mi:“MI:0915”(physical association)	0.670
ITCH	NEDD9	psi-mi:“MI:0915”(physical association)	0.580
NEDD9	ITCH	psi-mi:“MI:0915”(physical association)	0.580
NEDD9	NFKBIA	psi-mi:“MI:0915”(physical association)	0.560
NEDD9	PRR20C	psi-mi:“MI:0915”(physical association)	0.560
REL	NEDD9	psi-mi:“MI:0915”(physical association)	0.560
NEDD9	TRIP6	psi-mi:“MI:0915”(physical association)	0.560
RFX6	NEDD9	psi-mi:“MI:0915”(physical association)	0.560
RBPMS	NEDD9	psi-mi:“MI:0915”(physical association)	0.560
PRR20C	NEDD9	psi-mi:“MI:0915”(physical association)	0.560
NEDD9	REL	psi-mi:“MI:0915”(physical association)	0.560
NEDD9	RFX6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (129): NEDD9 (Two-hybrid), NFKBIA (Two-hybrid), REL (Two-hybrid), TRIM27 (Two-hybrid), TRIP6 (Two-hybrid), BCAR3 (Two-hybrid), RBPMS (Two-hybrid), BANP (Two-hybrid), PRR20A (Two-hybrid), RFX6 (Two-hybrid), NEDD9 (Reconstituted Complex), NEDD9 (Affinity Capture-Western), FZR1 (Reconstituted Complex), AURKA (Reconstituted Complex), FZR1 (Reconstituted Complex)

ESM2 similar proteins: A0A8I3PDQ1, A0M8S4, A0M8T5, A5GFW5, B6RSP1, B9EJA2, D4A039, E9Q0S6, O00750, O35177, Q00PJ1, Q07DV1, Q07DW4, Q07DX4, Q07DY4, Q07E15, Q07E28, Q07E41, Q08EC4, Q09YG9, Q09YI1, Q09YK4, Q09YM8, Q108T9, Q14511, Q155Q3, Q2IBA2, Q2IBB2, Q2IBD4, Q2IBE6, Q2IBF7, Q2QL82, Q2QLA2, Q2QLB3, Q2QLF8, Q2QLG9, Q2VUH7, Q3UIL6, Q5JV73, Q61140

Diamond homologs: A0A8I3PDQ1, A1CEK6, A1DFN5, A2QW93, A4FU49, A4RF61, A7A261, O13736, O35177, O35179, O35964, O42287, O43281, P29355, P34109, P38753, P43603, P56945, Q08012, Q0CJU8, Q0P5B1, Q0U6X7, Q14511, Q15811, Q16584, Q1E878, Q2GT05, Q4R729, Q4WHP5, Q557J6, Q5BBL4, Q5I1X5, Q61140, Q62419, Q62420, Q63767, Q64355, Q66HA1, Q6BNP6, Q6C2N2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NEDD9	“up-regulates activity”	AURKA	binding
AURKA	“up-regulates activity”	NEDD9	phosphorylation
PTPN11	“down-regulates activity”	NEDD9	dephosphorylation
AXL	“up-regulates activity”	NEDD9	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
small GTPase-mediated signal transduction	5	29.5×	3e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

113 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	88
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1166 predictions. Top by Δscore:

Variant	Effect	Δscore
6:11185667:CTCAG:C	acceptor_gain	1.0000
6:11185668:TCAG:T	acceptor_gain	1.0000
6:11185669:CAG:C	acceptor_gain	1.0000
6:11185669:CAGC:C	acceptor_gain	1.0000
6:11185670:AG:A	acceptor_gain	1.0000
6:11185670:AGCTG:A	acceptor_loss	1.0000
6:11185671:GC:G	acceptor_loss	1.0000
6:11185672:C:CA	acceptor_loss	1.0000
6:11185672:C:CC	acceptor_gain	1.0000
6:11185675:C:CT	acceptor_gain	1.0000
6:11185676:A:T	acceptor_gain	1.0000
6:11188213:CTTA:C	donor_loss	1.0000
6:11188214:TTACC:T	donor_loss	1.0000
6:11188215:TACCT:T	donor_loss	1.0000
6:11188216:A:AC	donor_gain	1.0000
6:11188216:A:AG	donor_loss	1.0000
6:11188217:C:A	donor_loss	1.0000
6:11188217:C:CC	donor_gain	1.0000
6:11188304:TACC:T	acceptor_gain	1.0000
6:11188307:CCTGT:C	acceptor_gain	1.0000
6:11188316:T:C	acceptor_gain	1.0000
6:11189958:TTTTA:T	donor_loss	1.0000
6:11189959:TTTA:T	donor_loss	1.0000
6:11189960:TTA:T	donor_loss	1.0000
6:11189961:TA:T	donor_loss	1.0000
6:11189962:A:C	donor_loss	1.0000
6:11189963:CCTGT:C	donor_loss	1.0000
6:11191206:C:CA	acceptor_loss	1.0000
6:11191207:T:C	acceptor_loss	1.0000
6:11192339:A:AC	donor_gain	1.0000

AlphaMissense

5496 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:11213564:C:G	R59P	1.000
6:11213565:G:C	R59G	1.000
6:11213566:G:C	N58K	1.000
6:11213566:G:T	N58K	1.000
6:11213570:C:T	G57D	1.000
6:11213573:G:T	P56Q	1.000
6:11213576:A:T	V55D	1.000
6:11213583:C:G	G53R	1.000
6:11213601:A:G	S47P	1.000
6:11213602:G:C	C46W	1.000
6:11213603:C:T	C46Y	1.000
6:11213604:A:G	C46R	1.000
6:11213606:A:G	L45P	1.000
6:11213610:A:G	W44R	1.000
6:11213610:A:T	W44R	1.000
6:11213611:C:A	W43C	1.000
6:11213611:C:G	W43C	1.000
6:11213613:A:G	W43R	1.000
6:11213613:A:T	W43R	1.000
6:11213616:C:G	G42R	1.000
6:11213616:C:T	G42R	1.000
6:11213645:A:T	V32D	1.000
6:11213651:A:G	L30P	1.000
6:11213668:A:C	F24L	1.000
6:11213668:A:T	F24L	1.000
6:11213669:A:G	F24S	1.000
6:11213670:A:G	F24L	1.000
6:11213675:A:G	L22P	1.000
6:11213675:A:T	L22Q	1.000
6:11213698:A:C	N14K	1.000

dbSNP variants (sampled 300 via entrez): RS1000001312 (6:11363395 T>C), RS1000007932 (6:11218138 G>A), RS1000020362 (6:11258879 T>C,G), RS1000059278 (6:11195006 A>G), RS1000061233 (6:11358998 C>A,T), RS1000075214 (6:11301898 A>C), RS1000078602 (6:11302182 A>G), RS1000095568 (6:11376688 T>G), RS1000109676 (6:11195299 T>C), RS1000142059 (6:11303178 C>A,G,T), RS1000142600 (6:11235140 C>A,T), RS1000158440 (6:11253222 C>G), RS1000170025 (6:11236655 G>C), RS1000170841 (6:11284842 C>A,T), RS1000179088 (6:11354855 G>A)

Disease associations

OMIM: gene MIM:602265 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001353_2	HIV-1 susceptibility	2.000000e-06
GCST002606_11	Prostate cancer	4.000000e-08
GCST002606_30	Prostate cancer	3.000000e-09
GCST004746_34	Small cell lung carcinoma	4.000000e-06
GCST005196_91	Coronary artery disease	4.000000e-07
GCST006193_95	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-08
GCST006194_4	Diastolic blood pressure x smoking status (current vs non-current) interaction (1df test)	6.000000e-06
GCST006311_1	Childhood dental caries in permanent teeth	2.000000e-08
GCST006976_17	Macular thickness	3.000000e-25

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

114 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	8
Benzo(a)pyrene	decreases expression, increases expression, affects methylation	6
bisphenol A	affects expression, decreases expression, decreases methylation	5
Estradiol	increases expression, decreases expression, affects expression, affects cotreatment	5
Cadmium Chloride	affects expression, decreases expression, increases expression	5
methylmercuric chloride	affects cotreatment, increases expression	4
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	4
Cisplatin	increases reaction, increases expression, affects response to substance, decreases expression	4
Tretinoin	increases expression, decreases reaction	4
Valproic Acid	affects expression, increases expression	4
Cyclosporine	decreases expression, decreases methylation	4
cobaltous chloride	decreases expression	2
entinostat	decreases expression, increases expression, affects cotreatment	2
Vorinostat	increases expression, decreases expression	2
Diuron	decreases expression	2
Oxygen	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression, decreases expression	2
Smoke	decreases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
Particulate Matter	increases abundance, decreases expression	2
FR900359	decreases phosphorylation	1
sotorasib	affects cotreatment, increases expression	1
geldanamycin	increases expression	1
4-oxoretinoic acid	increases expression	1
chloroacetaldehyde	decreases expression	1
ethylbenzene	increases expression	1
triphenyl phosphate	affects expression	1
withaferin A	affects binding, decreases reaction, increases phosphorylation	1
2-methyl-4-isothiazolin-3-one	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.