NCK2

Summary

NCK2 (NCK adaptor protein 2, HGNC:7665) is a protein-coding gene on chromosome 2q12.2, encoding Cytoplasmic protein NCK2 (O43639). Adapter protein which associates with tyrosine-phosphorylated growth factor receptors or their cellular substrates.

This gene encodes a member of the NCK family of adaptor proteins. The protein contains three SH3 domains and one SH2 domain. The protein has no known catalytic function but has been shown to bind and recruit various proteins involved in the regulation of receptor protein tyrosine kinases. It is through these regulatory activities that this protein is believed to be involved in cytoskeletal reorganization. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 8440 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 37 total
• MANE Select transcript: NM_003581

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7665
Approved symbol	NCK2
Name	NCK adaptor protein 2
Location	2q12.2
Locus type	gene with protein product
Status	Approved
Aliases	NCKbeta
Ensembl gene	ENSG00000071051
Ensembl biotype	protein_coding
OMIM	604930
Entrez	8440

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 35 protein_coding

ENST00000233154, ENST00000393348, ENST00000393349, ENST00000425756, ENST00000451463, ENST00000522586, ENST00000899654, ENST00000899655, ENST00000899656, ENST00000899657, ENST00000899658, ENST00000899659, ENST00000899660, ENST00000899661, ENST00000940636, ENST00000940637, ENST00000940638, ENST00000940639, ENST00000940640, ENST00000940641, ENST00000958274, ENST00000958275, ENST00000958276, ENST00000958277, ENST00000958278, ENST00000958279, ENST00000958280, ENST00000958281, ENST00000958282, ENST00000958283, ENST00000958284, ENST00000958285, ENST00000958286, ENST00000958287, ENST00000958288

RefSeq mRNA: 3 — MANE Select: NM_003581 NM_001004720, NM_001004722, NM_003581

CCDS: CCDS33266

Canonical transcript exons

ENST00000233154 — 5 exons

Exon	Start	End
ENSE00000527533	105881328	105882049
ENSE00000999675	105855048	105855289
ENSE00001471488	105816430	105816613
ENSE00001471491	105744912	105745138
ENSE00001936033	105892982	105894272

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8539 / max 178.4977, expressed in 1774 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21816	9.7588	1705
21815	2.8808	1398
21819	0.2070	51
21820	0.0073	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.26	gold quality
lower esophagus mucosa	UBERON:0035834	97.10	gold quality
hair follicle	UBERON:0002073	96.80	gold quality
parotid gland	UBERON:0001831	96.50	gold quality
secondary oocyte	CL:0000655	96.17	gold quality
CA1 field of hippocampus	UBERON:0003881	95.73	gold quality
ganglionic eminence	UBERON:0004023	95.65	gold quality
cartilage tissue	UBERON:0002418	95.43	gold quality
duodenum	UBERON:0002114	95.13	gold quality
tongue squamous epithelium	UBERON:0006919	94.94	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.91	gold quality
mucosa of stomach	UBERON:0001199	94.84	gold quality
gingiva	UBERON:0001828	94.84	gold quality
jejunal mucosa	UBERON:0000399	94.80	gold quality
esophagus mucosa	UBERON:0002469	94.78	gold quality
gingival epithelium	UBERON:0001949	94.67	gold quality
ileal mucosa	UBERON:0000331	94.57	gold quality
diaphragm	UBERON:0001103	94.50	silver quality
embryo	UBERON:0000922	94.33	gold quality
amniotic fluid	UBERON:0000173	94.26	gold quality
epithelium of esophagus	UBERON:0001976	94.20	gold quality
esophagus	UBERON:0001043	94.13	gold quality
esophagus squamous epithelium	UBERON:0006920	94.04	gold quality
nasal cavity epithelium	UBERON:0005384	93.94	gold quality
tibialis anterior	UBERON:0001385	93.92	silver quality
mononuclear cell	CL:0000842	93.80	gold quality
monocyte	CL:0000576	93.79	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.70	gold quality
lower esophagus	UBERON:0013473	93.66	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.79

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
HSP90B1	Repression
PPP1R15A	Repression

Upstream regulators (CollecTRI, top): AP1

miRNA regulators (miRDB)

71 targeting NCK2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6875-3P	99.82	70.26	2983

Literature-anchored findings (GeneRIF, showing 29)

• Nck-2 interacts with focal adhesion kinase and modulates cell motility. Using a mutational strategy, the formation of the Nck-2-FAK complex is mediated by interactions involving multiple SH2 and SH3 domains of Nck-2. (PMID:11950595)
• Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. (PMID:12110186)
• analysis of binding between the Tyr-phosphorylated human ephrinB2 and Nck2 SH2 domain (PMID:15764601)
• Molecular model of the first SRC homology 3 domain of Nck2. (PMID:16604428)
• Nck1 (Nckalpha) and Nck2 (Nckbeta and Grb4): binding specificities of both SH2 domains are essentially indistinguishable (PMID:16636066)
• determined the NMR structures and dynamic properties of the hNck2 SH3 domains and to define their ligand binding preferences with nine proline-rich peptides derived from Wire, CAP-1, CAP-2, Prk, Wrch1, Wrch2, and Nogo (PMID:16752908)
• Data show that Nck (isoforms 1 and 2) as a component of the CReP/PP1c holophosphatase complex contributes to maintain eIF2alpha in a hypophosphorylated state, and modulates translation and eIF2alpha signaling in response to ER stress. (PMID:16835242)
• Demonstrate connection between septins/SOCS7/NCK signaling and the DNA damage response. (PMID:17803907)
• the adaptors Nck and ShcA influenced adherence of S. Typhimurium to non-phagocytic cells. (PMID:17906149)
• Data show that Nck forms a complex with an atypical PxxDY motif of the CD3epsilon tail, which encompasses Tyr166 within the activation motif and a T-cell receptor endocytosis signal. (PMID:18555270)
• Results point to NCK2 as a disease candidate gene and further supports the GLC1B locus as an important genomic region that is associated with the genetic predisposition to glaucoma. (PMID:18723748)
• independent roles and mechanisms of action of Nckalpha and Nckbeta in dermal fibroblast migration, which is critical for wound healing. (PMID:19242519)
• biophysical analysis of Nck2 SH3 domain (PMID:19956763)
• Nck2 is an adaptor protein composed of 3N-SH3 domains followed by a unique Cterminal SH2 domain. It interacts with PINCH in integrin signal transduction, cell migratio and survival. Review. (PMID:21880263)
• p21-Activated kinase 3 (PAK3) protein regulates synaptic transmission through its interaction with the Nck2/Grb4 protein adaptor. (PMID:21949127)
• Nck2 effectively influences human melanoma phenotype progression. (PMID:21992144)
• Data show that both HK2 and NCK2 are expressed in the retinal ganglion cell layer. (PMID:23349798)
• The hNck2 SH3 domain also exhibited pH dependent monomer-dimer transition. (PMID:23524290)
• NCK2 is involved in the susceptibility to opiates addiction. (PMID:23533358)
• Proteasomal degradation of Nck1 but not Nck2 regulates RhoA activation and actin dynamics. (PMID:24287595)
• Tir-Intimin interaction recruits the Nck adaptor to a Tir tyrosine phosphorylated residue where it activates neural Wiskott-Aldrich syndrome protein (N-WASP). (PMID:25482634)
• Data suggest that PINCH1 and Nck2 critically participate in the regulation of cellular radiosensitivity and EGFR function and downstream signaling in a cellular model of human squamous cell carcinoma. (PMID:26004008)
• Nck1 and Nck2 Interact with WTIP. Nck1/2 integrates nephrin with the Hippo kinase cascade through association with the adaptor protein WTIP. (PMID:27033705)
• This study provides evidence of a possible role of NCK2 as biomarker of ovarian cancer progression. (PMID:29218693)
• There was no difference in the Nck2 mRNA expression between the SLE patients and the healthy subjects. (PMID:29911835)
• The minor allele frequency (MAF) of rs678350 was significantly higher in NTG patients (MAF = 0.32) than in controls (MAF = 0.23) (OR, 1.586; 95% CI, 1.058 to 2.375; P = 0.028). This trend was more significant in the dominant model (OR, 1.908; 95% CI, 1.144 to 3.180; P = 0.015). (PMID:31512042)
• Nck adapter proteins promote podosome biogenesis facilitating extracellular matrix degradation and cancer invasion. (PMID:31638742)
• Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling. (PMID:33917227)
• [CBL inhibits proliferation and invasion of breast cancer cells by ubiquitylation-mediated degradation of NCK2]. (PMID:36504051)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nck2a	ENSDARG00000018206
danio_rerio	nck2b	ENSDARG00000043361
mus_musculus	Nck2	ENSMUSG00000066877
rattus_norvegicus	Nck2	ENSRNOG00000017155
drosophila_melanogaster	dock	FBGN0010583
caenorhabditis_elegans		WBGENE00006410

Paralogs (9): DAPP1 (ENSG00000070190), GRAP2 (ENSG00000100351), SLA2 (ENSG00000101082), GRAP (ENSG00000154016), SLA (ENSG00000155926), NCK1 (ENSG00000158092), GRB2 (ENSG00000177885), GRAPL (ENSG00000189152), SH2D5 (ENSG00000189410)

Protein

Protein identifiers

Cytoplasmic protein NCK2 — O43639 (reviewed: O43639)

Alternative names: Growth factor receptor-bound protein 4, NCK adaptor protein 2, SH2/SH3 adaptor protein NCK-beta

All UniProt accessions (5): O43639, A0A0S2Z4M6, E7EPF5, E7ERP6, E9PEE2

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein which associates with tyrosine-phosphorylated growth factor receptors or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.

Subunit / interactions. Interacts with DOCK1, LIMS1 and TGFB1I1. Part of a complex containing PPP1R15B, PP1 and NCK2. Interacts with FASLG. Interacts with AXL. Interacts with PAK1, PKN2 and SOS1. Interacts (via SH2 domain) with EGFR. Interacts (via SH2 domain) with DDR1. Interacts with IRS1.

Subcellular location. Cytoplasm. Endoplasmic reticulum.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated.

RefSeq proteins (3): NP_001004720, NP_001004722, NP_003572* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001452	SH3_domain	Domain
IPR017304	NCK	Family
IPR035559	Nck2_SH3_1	Domain
IPR035560	Nck2_SH3_2	Domain
IPR035561	Nck2_SH3_3	Domain
IPR035883	Nck2_SH2	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051184	Tyrosine-phos_adapter	Family

Pfam: PF00017, PF00018, PF14604

UniProt features (49 total): strand 26, modified residue 5, domain 4, sequence conflict 3, helix 3, turn 3, mutagenesis site 2, initiator methionine 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
2CIA	X-RAY DIFFRACTION	1.45
4E6R	X-RAY DIFFRACTION	2.2
1U5S	SOLUTION NMR
1WX6	SOLUTION NMR
1Z3K	SOLUTION NMR
2B86	SOLUTION NMR
2FRW	SOLUTION NMR
2FRY	SOLUTION NMR
2JXB	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43639-F1	72.16	0.18

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 (5): 94, 110, 2, 90, 92

Mutagenesis-validated functional residues (2):

Position	Phenotype
148	abolishes interaction with dock1.
234	abolishes interaction with dock1 and irs1.

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-186763	Downstream signal transduction
R-HSA-373753	Nephrin family interactions
R-HSA-3928664	Ephrin signaling
R-HSA-428540	Activation of RAC1
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-8985801	Regulation of cortical dendrite branching
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013424	RHOV GTPase cycle
R-HSA-1266738	Developmental Biology
R-HSA-1500931	Cell-Cell communication
R-HSA-162582	Signal Transduction
R-HSA-186797	Signaling by PDGF
R-HSA-194138	Signaling by VEGF
R-HSA-194315	Signaling by Rho GTPases
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-376176	Signaling by ROBO receptors
R-HSA-422475	Axon guidance
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 432 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, chr2q12, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_TRANSLATIONAL_INITIATION, GOBP_NEUROGENESIS, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION

GO Biological Process (23): negative regulation of transcription by RNA polymerase II (GO:0000122), immunological synapse formation (GO:0001771), actin filament organization (GO:0007015), signal transduction (GO:0007165), signal complex assembly (GO:0007172), epidermal growth factor receptor signaling pathway (GO:0007173), negative regulation of cell population proliferation (GO:0008285), cell migration (GO:0016477), lamellipodium assembly (GO:0030032), positive regulation of actin filament polymerization (GO:0030838), regulation of translation initiation in response to endoplasmic reticulum stress (GO:0036491), positive regulation of translation in response to endoplasmic reticulum stress (GO:0036493), positive regulation of T cell proliferation (GO:0042102), T cell activation (GO:0042110), positive regulation of transcription by RNA polymerase II (GO:0045944), ephrin receptor signaling pathway (GO:0048013), dendritic spine development (GO:0060996), positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902237), negative regulation of PERK-mediated unfolded protein response (GO:1903898), regulation of transcription by RNA polymerase II (GO:0006357), regulation of translation (GO:0006417), positive regulation of macromolecule biosynthetic process (GO:0010557), response to endoplasmic reticulum stress (GO:0034976)

GO Molecular Function (8): phosphotyrosine residue binding (GO:0001784), cytoskeletal adaptor activity (GO:0008093), signaling receptor complex adaptor activity (GO:0030159), receptor tyrosine kinase binding (GO:0030971), signaling adaptor activity (GO:0035591), protein-containing complex binding (GO:0044877), scaffold protein binding (GO:0097110), protein binding (GO:0005515)

GO Cellular Component (6): cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), vesicle membrane (GO:0012506), postsynaptic density (GO:0014069), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Signaling by ROBO receptors	2
RHO GTPase cycle	2
Signaling by Receptor Tyrosine Kinases	2
Axon guidance	2
Signaling by PDGF	1
Cell-Cell communication	1
EPH-Ephrin signaling	1
Signaling by VEGF	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Nervous system development	1
Signal Transduction	1
Signaling by Rho GTPases	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
regulation of transcription by RNA polymerase II	2
lymphocyte activation	2
response to endoplasmic reticulum stress	2
regulation of translation in response to endoplasmic reticulum stress	2
protein-macromolecule adaptor activity	2
signaling receptor binding	2
binding	2
cellular anatomical structure	2
cytoplasm	2
negative regulation of DNA-templated transcription	1
cell-cell recognition	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of signal transduction	1
protein-containing complex assembly	1
ERBB signaling pathway	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell motility	1
lamellipodium organization	1
plasma membrane bounded cell projection assembly	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
translational initiation	1
regulation of translational initiation in response to stress	1
translation	1
positive regulation of translation in response to stress	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1

Protein interactions and networks

STRING

1400 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCK2	LIMS1	P48059	990
NCK2	EFNB1	P98172	962
NCK2	NPHS1	O60500	903
NCK2	EFNB3	Q15768	871
NCK2	ILK	P57043	856
NCK2	IRS1	P35568	827
NCK2	WASL	O00401	803
NCK2	EFNB2	P52799	803
NCK2	DOCK1	Q14185	796
NCK2	GIT1	Q9Y2X7	795
NCK2	PARVA	Q9NVD7	777
NCK2	WAS	P42768	772
NCK2	EPHA4	P54764	763
NCK2	CRK	P46108	755
NCK2	ABI1	Q8IZP0	744

IntAct

659 interactions, top by confidence:

A	B	Type	Score
NCK2	PAK1	psi-mi:“MI:0915”(physical association)	0.940
PAK1	NCK2	psi-mi:“MI:0915”(physical association)	0.940
NCK2	CBLB	psi-mi:“MI:0915”(physical association)	0.900
CBLB	NCK2	psi-mi:“MI:0915”(physical association)	0.900
NCK2	CHN1	psi-mi:“MI:0915”(physical association)	0.890
CHN1	NCK2	psi-mi:“MI:0915”(physical association)	0.890
NCK2	WASL	psi-mi:“MI:0915”(physical association)	0.870
WASL	NCK2	psi-mi:“MI:0915”(physical association)	0.870
ABI2	NCK2	psi-mi:“MI:0915”(physical association)	0.850
NCK2	ABI2	psi-mi:“MI:0915”(physical association)	0.850

BioGRID (462): NCK2 (Reconstituted Complex), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid), NCK2 (Two-hybrid)

ESM2 similar proteins: A1ZAY1, A6NI72, A7MBL8, A8MVU1, F1M707, O08874, O15034, O43639, O55033, O75563, O77774, O88382, P14598, P15056, P15498, P16333, P27870, P28028, P54100, Q04982, Q08DN7, Q09014, Q16513, Q1KKZ1, Q1RMU2, Q32LP7, Q3UND0, Q5BKC9, Q5FVW6, Q5RDS2, Q5RDX5, Q5RED8, Q5RID7, Q5VUG0, Q66H62, Q69ZK0, Q80TQ2, Q80U40, Q86UL8, Q8BWW9

Diamond homologs: A0JNB0, A1A5H8, A1Y2K1, A6QLK6, F1LM93, F1RDG9, O43639, O45539, O55033, O75791, O89100, P00519, P00520, P00522, P00523, P00524, P00525, P00526, P00527, P03949, P05480, P06239, P06240, P06241, P07947, P07948, P08103, P08631, P09324, P09769, P10447, P10936, P12931, P13115, P13116, P13406, P14084, P14085, P14234, P15054

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
EGFR	up-regulates	NCK2	binding
PDGFRB	up-regulates	NCK2	binding
NTRK2	up-regulates	NCK2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of actin dynamics for phagocytic cup formation	5	25.6×	3e-04
RAC1 GTPase cycle	6	10.2×	1e-03
CDC42 GTPase cycle	5	10.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1726 predictions. Top by Δscore:

Variant	Effect	Δscore
2:105745139:GTA:G	donor_loss	1.0000
2:105745140:T:A	donor_loss	1.0000
2:105816425:TTTAG:T	acceptor_loss	1.0000
2:105816427:TAG:T	acceptor_loss	1.0000
2:105816428:A:AG	acceptor_gain	1.0000
2:105816428:AGAT:A	acceptor_loss	1.0000
2:105816429:G:A	acceptor_loss	1.0000
2:105816429:G:GG	acceptor_gain	1.0000
2:105816429:GATTT:G	acceptor_gain	1.0000
2:105816614:G:GG	donor_gain	1.0000
2:105816615:T:A	donor_loss	1.0000
2:105855042:T:A	acceptor_gain	1.0000
2:105855046:A:AG	acceptor_gain	1.0000
2:105855046:AGAAG:A	acceptor_gain	1.0000
2:105855047:G:GA	acceptor_gain	1.0000
2:105855047:GA:G	acceptor_gain	1.0000
2:105855047:GAA:G	acceptor_gain	1.0000
2:105855047:GAAGG:G	acceptor_gain	1.0000
2:105855287:TAGG:T	donor_loss	1.0000
2:105855288:AGGTG:A	donor_loss	1.0000
2:105855290:G:GG	donor_gain	1.0000
2:105855290:GT:G	donor_loss	1.0000
2:105855291:T:G	donor_loss	1.0000
2:105892978:CCA:C	acceptor_loss	1.0000
2:105892979:CA:C	acceptor_loss	1.0000
2:105892980:A:AC	acceptor_loss	1.0000
2:105892980:A:AG	acceptor_gain	1.0000
2:105892981:G:GG	acceptor_gain	1.0000
2:105745134:GCGAG:G	donor_gain	0.9900
2:105745136:GAG:G	donor_gain	0.9900

AlphaMissense

2501 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:105855089:C:A	A9D	1.000
2:105855094:T:A	W11R	1.000
2:105855094:T:C	W11R	1.000
2:105855096:G:C	W11C	1.000
2:105855096:G:T	W11C	1.000
2:105855100:T:C	Y13H	1.000
2:105855100:T:G	Y13D	1.000
2:105855121:G:A	E20K	1.000
2:105855125:T:C	L21P	1.000
2:105855149:T:C	L29P	1.000
2:105855155:T:C	L31S	1.000
2:105855175:T:A	W38R	1.000
2:105855175:T:C	W38R	1.000
2:105855176:G:C	W38S	1.000
2:105855177:G:C	W38C	1.000
2:105855177:G:T	W38C	1.000
2:105855178:T:A	W39R	1.000
2:105855178:T:C	W39R	1.000
2:105855180:G:C	W39C	1.000
2:105855180:G:T	W39C	1.000
2:105855208:G:C	G49R	1.000
2:105855209:G:A	G49D	1.000
2:105855209:G:T	G49V	1.000
2:105855215:T:A	V51E	1.000
2:105855217:C:A	P52T	1.000
2:105855217:C:T	P52S	1.000
2:105855218:C:A	P52Q	1.000
2:105855218:C:G	P52R	1.000
2:105855218:C:T	P52L	1.000
2:105855223:A:G	N54D	1.000

dbSNP variants (sampled 300 via entrez): RS1000021001 (2:105815111 C>A), RS1000032551 (2:105877041 C>A), RS1000034566 (2:105882584 A>C,G), RS1000043604 (2:105841876 A>G), RS1000050732 (2:105800945 G>A), RS1000091657 (2:105761973 G>A), RS1000109365 (2:105763048 A>G), RS1000122621 (2:105802432 T>G), RS1000172792 (2:105879547 C>T), RS1000222232 (2:105844192 A>C,G), RS1000242480 (2:105784632 T>A), RS1000250423 (2:105866498 G>A), RS1000269165 (2:105793264 GT>G,GTT), RS1000269562 (2:105767980 C>T), RS1000281725 (2:105866698 G>A)

Disease associations

OMIM: gene MIM:604930 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001880_1	Addiction	1.000000e-11
GCST001880_2	Addiction	2.000000e-11
GCST001880_3	Addiction	2.000000e-08
GCST002187_1	Systolic blood pressure in sickle cell anemia	1.000000e-06
GCST004616_129	Platelet distribution width	1.000000e-09
GCST90002395_335	Mean platelet volume	4.000000e-27
GCST90002401_382	Platelet distribution width	7.000000e-20
GCST90006886_1	Anti-chlamydia trachomatis IgG seropositivity	5.000000e-09
GCST90012877_26	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-12
GCST90012877_27	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0007984	platelet component distribution width
EFO:0009330	Chlamydia trachomatis seropositivity
EFO:0009268	family history of Alzheimer’s disease

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, decreases expression	2
aristolochic acid I	decreases reaction, increases expression	1
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation, affects cotreatment, decreases methylation	1
hydroxyhydroquinone	increases expression	1
benzo(e)pyrene	increases methylation	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	increases expression	1
ICG 001	increases expression	1
trans-10,cis-12-conjugated linoleic acid	decreases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Cadmium	decreases expression, increases abundance	1
Camptothecin	decreases expression	1
Cisplatin	decreases expression	1
Daunorubicin	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Etoposide	decreases expression	1
Hydrogen Peroxide	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Pesticides	decreases methylation	1
Theophylline	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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