NCK1

Summary

NCK1 (NCK adaptor protein 1, HGNC:7664) is a protein-coding gene on chromosome 3q22.3, encoding SH2/SH3 adapter protein NCK1 (P16333). Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates.

The protein encoded by this gene is one of the signaling and transforming proteins containing Src homology 2 and 3 (SH2 and SH3) domains. It is located in the cytoplasm and is an adaptor protein involved in transducing signals from receptor tyrosine kinases to downstream signal recipients such as RAS. Alternatively spliced transcript variants encoding different isoforms have been found.

Source: NCBI Gene 4690 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 20 total
• Druggable target: yes
• MANE Select transcript: NM_001291999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7664
Approved symbol	NCK1
Name	NCK adaptor protein 1
Location	3q22.3
Locus type	gene with protein product
Status	Approved
Aliases	NCKalpha
Ensembl gene	ENSG00000158092
Ensembl biotype	protein_coding
OMIM	600508
Entrez	4690

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 29 protein_coding, 3 retained_intron

ENST00000288986, ENST00000460960, ENST00000467911, ENST00000469404, ENST00000476286, ENST00000478862, ENST00000481752, ENST00000482071, ENST00000485096, ENST00000488930, ENST00000491539, ENST00000496489, ENST00000898712, ENST00000898713, ENST00000898714, ENST00000898715, ENST00000898716, ENST00000898717, ENST00000898718, ENST00000898719, ENST00000898720, ENST00000898721, ENST00000938741, ENST00000951209, ENST00000951210, ENST00000951211, ENST00000951212, ENST00000951213, ENST00000951214, ENST00000951215, ENST00000951216, ENST00000951217

RefSeq mRNA: 3 — MANE Select: NM_001291999 NM_001190796, NM_001291999, NM_006153

CCDS: CCDS3092, CCDS54644

Canonical transcript exons

ENST00000481752 — 4 exons

Exon	Start	End
ENSE00001036982	136945583	136946295
ENSE00001833930	136862208	136862353
ENSE00003794850	136927984	136928227
ENSE00003847271	136948259	136951606

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 96.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.6807 / max 349.8046, expressed in 1816 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38750	24.5363	1809
38751	9.7381	1749
38752	6.2589	770
38753	0.1475	86

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
penis	UBERON:0000989	96.78	gold quality
calcaneal tendon	UBERON:0003701	96.49	gold quality
esophagus squamous epithelium	UBERON:0006920	95.97	gold quality
oral cavity	UBERON:0000167	95.65	gold quality
epithelium of nasopharynx	UBERON:0001951	95.51	gold quality
nasopharynx	UBERON:0001728	95.49	gold quality
epithelium of esophagus	UBERON:0001976	94.39	gold quality
decidua	UBERON:0002450	93.99	gold quality
palpebral conjunctiva	UBERON:0001812	93.97	gold quality
tonsil	UBERON:0002372	93.95	gold quality
vagina	UBERON:0000996	93.86	gold quality
gingiva	UBERON:0001828	93.63	gold quality
esophagus mucosa	UBERON:0002469	93.63	gold quality
squamous epithelium	UBERON:0006914	93.60	gold quality
gingival epithelium	UBERON:0001949	93.53	gold quality
upper leg skin	UBERON:0004262	93.53	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.51	gold quality
endothelial cell	CL:0000115	93.47	gold quality
parietal pleura	UBERON:0002400	93.39	gold quality
pericardium	UBERON:0002407	93.32	gold quality
hair follicle	UBERON:0002073	93.18	gold quality
colonic mucosa	UBERON:0000317	93.07	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.89	gold quality
mammalian vulva	UBERON:0000997	92.79	gold quality
adipose tissue	UBERON:0001013	92.76	gold quality
lymph node	UBERON:0000029	92.74	gold quality
synovial joint	UBERON:0002217	92.68	gold quality
connective tissue	UBERON:0002384	92.59	gold quality
visceral pleura	UBERON:0002401	92.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
DDIT3	Repression
HSP90B1	Repression
PPP1R15A	Repression

miRNA regulators (miRDB)

173 targeting NCK1, 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-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394

Literature-anchored findings (GeneRIF, showing 40)

• Modulation of protein translation by Nck-1. (PMID:11959995)
• Grb2 and Nck act cooperatively to promote actin-based motility of vaccinia virus (PMID:12007418)
• The association of NCK with Wiskott-Aldrich syndrome protein is associated with cell migration in stromal cell-derived factor-1alpha-stimulated Jurkat cells (PMID:12135674)
• Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck: we propose that Rac1 and Nck cause dissociation of the WAVE1 complex, which releases active WAVE1-HSPC300 and leads to actin nucleation. (PMID:12181570)
• the interaction of the betaPIX.WASP.SPIN90 complex with Nck is crucial for stable cell adhesion and can be dynamically modulated by SPIN90 phosphorylation that is dependent on cell adhesion and ERK activation (PMID:14559906)
• Data show that clustering of Nck by a 12-residue Tir phosphopeptide is sufficient to trigger localized actin assembly. (PMID:14757753)
• Nck and Crk mediate distinct VEGF-induced signaling pathways that serve overlapping functions in cell migration. (PMID:15051508)
• Nck1 mediates endothelin A receptor-regulated cell migration through the Cdc42-dependent c-Jun N-terminal kinase pathway (PMID:15187089)
• nephrin phosphorylation results in Src kinase activation, recruitment of Nck, and assembly of actin filaments in an Nck-dependent fashion (PMID:16543952)
• FasL-associated adaptor protein Nck is involved in the actin-dependent transport of FasL-bearing secretory lysosomes to the mimunological synapse. (PMID:16595635)
• Nck1 (Nckalpha) and Nck2 (Nckbeta and Grb4): binding specificities of both SH2 domains are essentially indistinguishable (PMID:16636066)
• 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)
• overexpression of Nck in mammalian cells fails to attenuate eIF2alphaSer51 phosphorylation in response to amino acid starvation, a stress well known to activate GCN2 (PMID:17944934)
• Enteropathogenic Escherichia coli O125:H6 lacks the ability to utilize either Nck or TccP/TccP2 and hence triggers actin polymerization in vitro only inefficiently. (PMID:17984209)
• Any of 3 phosphorylated YDXV nephrin motifs is sufficient to recruit Nck via its SH2 domain & induce localized actin polymerization. Nck SH3 mutants in which only the 2d or 3d SH3 domain is functional can mediate nephrin-induced actin polymerization. (PMID:18212058)
• These data provide the first evidence identifying Nck-1 as a novel endogenous regulator of PKR and support the notion that Nck-1-PKR interaction could be a way to limit PKR activation. (PMID:18835251)
• Based on NMR data, CD3-epsilon-derived peptides bind Nckalpha SH3.1 through a PxxPxRDY motif that combines specific stabilising interactions corresponding to both canonical class II, PxxPx(K/R), and non-canonical PxxPxxDY motifs (PMID:18955169)
• independent roles and mechanisms of action of Nckalpha and Nckbeta in dermal fibroblast migration, which is critical for wound healing. (PMID:19242519)
• The results show that Bcr-Abl regulates the actin cytoskeleton and non-apoptotic membrane blebbing via a GADS/Slp-76/Nck1 adaptor protein pathway. (PMID:20079431)
• The novel ponsin isoform and its interaction with Nck1/2 provide exciting insight into the convergence of signalling pathways at the costameres, and its crucial role for skeletal muscle differentiation and re-generation. (PMID:20129698)
• Results define the composition, stoichiometry and specificity of interactions in the SLP-76, Nck and VAV1 complex, which is crucial for regulation of the actin machinery after T-cell activation. (PMID:20562827)
• Nck1 specifically localizes to invadopodia, but not to podosomes formed in macrophages or degradative structures formed in Src-transformed fibroblasts and PMA-stimulated endothelial cells. (PMID:20850195)
• Mass spectrometry analysis revealed a group of Nck1 SH2 domain-binding proteins that were differentially expressed in HCC. One of these proteins, dermcidin (DCD). (PMID:21397687)
• a functional cooperation between Nck and ADAP in stabilizing the recruitment of WASp to SLP76 regulates actin rearrangement. (PMID:21536650)
• Nck1 activates RasGAP by direct binding in the substrate-attached but not in the suspended cells. (PMID:21664272)
• Nck1 association with RasGAP depends on cell adhesion to the substrate. (PMID:21664272)
• Studies reveal for the first time that the adaptor protein Dock/Nck attenuates insulin signalling by recruiting PTP61F/PTP1B to its substrate, the IR. (PMID:21707536)
• Adapter protein Nck sequesters PAK1 in the cytoplasm and that coexpression of both PAK1 and Nck inhibits the amplifying effect of PRL-induced PAK1 on cyclin D1 promoter activity. (PMID:21719533)
• Nck1 is an adaptor protein composed of 3 N-terminal SH3 domains followed by a unique Cterminal SH2 domain. It plays a role in cell migration, cell adhesion, actin polymerization, stress responses and cell survival. It is implicated in melanoma. Review. (PMID:21880263)
• Decreased Nck1 protein in Jurkat T cells resulted in an impairment of TCR-CD3-mediated activation involving a defective Erk phosphorylation pathway. (PMID:22132889)
• the negative loop on p38 is mediated by c-ABL phosphorylation at tyrosine 105 of the adaptor protein NCK1, while the phosphorylation at tyrosine 209 of GRB2 down-modulates ERK1/2 and JNKs signaling. (PMID:22327338)
• both T cell activation and the association between SLP-76 and Nck. After T cell receptor stimulation, SLP-76 was phosphorylated, which enabled the binding of Nck. (PMID:22534133)
• The results indicate that the density of Nck molecules in aggregates is a critical determinant of actin polymerization. (PMID:22613834)
• LRFN4 complexed with 14-3-3s and NCK1 to mediate elongation in monocytic cells via Rac-1-mediated actin cytoskeleton reorganization (PMID:22677168)
• The results suggest that MNT, via interaction with Nck1, inhibits hepatoma cell migration. (PMID:22964333)
• we have optimized the GST-Nck1-SH2 pull-down procedure to obtain tyrosine-phosphorylated proteins in tumor tissues (PMID:23426619)
• The study identifies Nck as a key coordinator of cytoskeletal changes that enable cell polarization and directional migration, which are crucial processes in development and disease. (PMID:23444376)
• NCK1 plays a pivotal role in integrating endoplasmic reticulum stress signals on cancer cell survival. (PMID:23448571)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nck1a	ENSDARG00000074262
danio_rerio	nck1b	ENSDARG00000075369
mus_musculus	Nck1	ENSMUSG00000032475
rattus_norvegicus	Nck1	ENSRNOG00000014917
drosophila_melanogaster	dock	FBGN0010583
caenorhabditis_elegans		WBGENE00006410

Paralogs (9): DAPP1 (ENSG00000070190), NCK2 (ENSG00000071051), GRAP2 (ENSG00000100351), SLA2 (ENSG00000101082), GRAP (ENSG00000154016), SLA (ENSG00000155926), GRB2 (ENSG00000177885), GRAPL (ENSG00000189152), SH2D5 (ENSG00000189410)

Protein

Protein identifiers

SH2/SH3 adapter protein NCK1 — P16333 (reviewed: P16333)

Alternative names: Cytoplasmic protein NCK1, NCK adapter protein 1, SH2/SH3 adapter protein NCK-alpha

All UniProt accessions (8): A0A0S2Z4Y3, C9J0K5, C9J869, C9JAB9, C9JVV5, C9K098, P16333, H7C5C7

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in the DNA damage response, not in the detection of the damage by ATM/ATR, but for efficient activation of downstream effectors, such as that of CHEK2. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling. Modulates the activation of EIF2AK2/PKR by dsRNA. May play a role in cell adhesion and migration through interaction with ephrin receptors.

Subunit / interactions. Interacts (via SH2 domain and SH3 domain 2) with EGFR. Interacts with PAK1 and SOS1. Interacts (via SH3 domains) with PKN2. Associates with BLNK, PLCG1, VAV1 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with SOCS7. This interaction is required for nuclear import. Part of a complex containing PPP1R15B, PP1 and NCK1. Interacts with RALGPS1. Interacts with CAV2 (tyrosine phosphorylated form). Interacts with ADAM15. Interacts with FASLG. Directly interacts with RASA1. Interacts with isoform 4 of MINK1. Interacts with FLT1 (tyrosine phosphorylated). Interacts with KDR (tyrosine phosphorylated). Interacts (via SH2 domain) with EPHB1; activates the JUN cascade to regulate cell adhesion. Interacts with EPHA2. Interacts (via SH2 domain) with PDGFRB (tyrosine phosphorylated). Interacts with the inactive form of EIF2AK2/PKR. Interacts with PTPN1. Interacts with INSR/insulin receptor (in response to insulin stimulation); This interaction may mediate PTPN1 recruitment leading to INSR dephosphorylation. Interacts with IRS1.

Subcellular location. Cytoplasm. Endoplasmic reticulum. Nucleus.

Post-translational modifications. Phosphorylated on Ser and Tyr residues. Phosphorylated in response to activation of EGFR and FcERI. Phosphorylated by activated PDGFRB.

Domain organisation. Only the first and third SH3 domains seem to be involved in RASA1-binding; the second SH3 domain and the SH2 domains do not seem to be involved.

Isoforms (2)

UniProt ID	Names	Canonical?
P16333-1	1	yes
P16333-2	2

RefSeq proteins (3): NP_001177725, NP_001278928, NP_006144 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001452	SH3_domain	Domain
IPR017304	NCK	Family
IPR035562	Nck1_SH3_1	Domain
IPR035564	Nck1_SH3_2	Domain
IPR035565	Nck1_SH3_3	Domain
IPR035882	Nck1_SH2	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051184	Tyrosine-phos_adapter	Family

Pfam: PF00017, PF00018

UniProt features (44 total): strand 20, modified residue 7, helix 5, mutagenesis site 4, domain 4, initiator methionine 1, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
5QU8	X-RAY DIFFRACTION	0.93
5QU3	X-RAY DIFFRACTION	1.02
5QU2	X-RAY DIFFRACTION	1.04
5QU4	X-RAY DIFFRACTION	1.05
5QU1	X-RAY DIFFRACTION	1.08
5QU5	X-RAY DIFFRACTION	1.11
5QU7	X-RAY DIFFRACTION	1.27
2CI9	X-RAY DIFFRACTION	1.5
5QUA	X-RAY DIFFRACTION	1.51
2CI8	X-RAY DIFFRACTION	1.8
5QU6	X-RAY DIFFRACTION	1.82
2CUB	SOLUTION NMR
2JS0	SOLUTION NMR
2JS2	SOLUTION NMR
2JW4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16333-F1	71.90	0.15

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 (7): 96, 105, 166, 2, 85, 89, 91

Mutagenesis-validated functional residues (4):

Position	Phenotype
38	small decrease in rasa1-binding. almost complete loss of rasa1-binding; when associated with k-143 and k-229.
143	no effect on rasa1-binding. almost complete loss of rasa1-binding; when associated with k-38 and k-229.
229	small decrease in rasa1-binding. almost complete loss of rasa1-binding; when associated with k-38 and k-229.
308	no effect on rasa1-binding.

Function

Pathways and Gene Ontology

Reactome pathways

45 pathways

ID	Pathway
R-HSA-186763	Downstream signal transduction
R-HSA-202433	Generation of second messenger molecules
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-373753	Nephrin family interactions
R-HSA-418885	DCC mediated attractive signaling
R-HSA-428540	Activation of RAC1
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5663213	RHO GTPases Activate WASPs and WAVEs
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013424	RHOV GTPase cycle
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9833482	PKR-mediated signaling
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
R-HSA-1169410	Antimicrobial mechanism of IFN-stimulated genes
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-1500931	Cell-Cell communication
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-186797	Signaling by PDGF
R-HSA-194138	Signaling by VEGF
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-202403	TCR signaling
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis
R-HSA-373752	Netrin-1 signaling

MSigDB gene sets: 466 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, BROWNE_HCMV_INFECTION_6HR_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, HOFMANN_CELL_LYMPHOMA_UP

GO Biological Process (29): negative regulation of transcription by RNA polymerase II (GO:0000122), substrate-dependent cell migration, cell extension (GO:0006930), actin filament organization (GO:0007015), signal complex assembly (GO:0007172), positive regulation of neuron projection development (GO:0010976), cell migration (GO:0016477), lamellipodium assembly (GO:0030032), regulation of cell migration (GO:0030334), positive regulation of actin filament polymerization (GO:0030838), response to endoplasmic reticulum stress (GO:0034976), 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), negative regulation of insulin receptor signaling pathway (GO:0046627), ephrin receptor signaling pathway (GO:0048013), negative regulation of T cell receptor signaling pathway (GO:0050860), antiviral innate immune response (GO:0140374), positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902237), positive regulation of cap-dependent translational initiation (GO:1903676), positive regulation of cap-independent translational initiation (GO:1903679), 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), positive regulation of MAPK cascade (GO:0043410), T cell receptor signaling pathway (GO:0050852), response to other organism (GO:0051707)

GO Molecular Function (14): protein kinase inhibitor activity (GO:0004860), signaling receptor binding (GO:0005102), cytoskeletal adaptor activity (GO:0008093), protein domain specific binding (GO:0019904), signaling receptor complex adaptor activity (GO:0030159), protein-macromolecule adaptor activity (GO:0030674), receptor tyrosine kinase binding (GO:0030971), signaling adaptor activity (GO:0035591), cadherin binding (GO:0045296), ephrin receptor binding (GO:0046875), eukaryotic initiation factor eIF2 binding (GO:0071074), protein sequestering activity (GO:0140311), molecular condensate scaffold activity (GO:0140693), protein binding (GO:0005515)

GO Cellular Component (9): protein phosphatase type 1 complex (GO:0000164), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), ribosome (GO:0005840), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), vesicle membrane (GO:0012506)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
RHO GTPase cycle	2
Immune System	2
Signaling by PDGF	1
TCR signaling	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
Cell-Cell communication	1
Netrin-1 signaling	1
Signaling by ROBO receptors	1
Signaling by VEGF	1
RHO GTPase Effectors	1
Leishmania phagocytosis	1
SARS-CoV Infections	1
Antimicrobial mechanism of IFN-stimulated genes	1
Signaling by the B Cell Receptor (BCR)	1
Interferon Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
protein-macromolecule adaptor activity	3
signaling receptor binding	3
cytoplasm	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
plasma membrane bounded cell projection assembly	2
response to endoplasmic reticulum stress	2
regulation of translation in response to endoplasmic reticulum stress	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
substrate-dependent cell migration	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
regulation of signal transduction	1
protein-containing complex assembly	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
cell motility	1
lamellipodium organization	1
cell migration	1
regulation of cell motility	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
cellular response to stress	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
positive regulation of T cell activation	1
lymphocyte activation	1
positive regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

2307 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCK1	WASL	O00401	998
NCK1	WAS	P42768	998
NCK1	WIPF1	O43516	997
NCK1	LCP2	Q13094	995
NCK1	NPHS1	O60500	994
NCK1	VAV1	P15498	988
NCK1	GRB2	P29354	985
NCK1	NCKIPSD	Q9NZQ3	980
NCK1	TNIK	Q9UKE5	980
NCK1	SHC1	P29353	969
NCK1	GRAP2	O75791	963
NCK1	CRK	P46108	956
NCK1	CDC42	P21181	956
NCK1	HCLS1	P14317	955
NCK1	CTTN	Q14247	955

IntAct

508 interactions, top by confidence:

A	B	Type	Score
NCK1	SOS1	psi-mi:“MI:0915”(physical association)	0.760
ABL2	NCK1	psi-mi:“MI:0915”(physical association)	0.730
NCK1	SOS2	psi-mi:“MI:0915”(physical association)	0.670
CEP170	KIF2A	psi-mi:“MI:2364”(proximity)	0.650
MAP4K1	NCK1	psi-mi:“MI:0915”(physical association)	0.650
NCK1	ASAP1	psi-mi:“MI:0915”(physical association)	0.610
NCK1	SHANK3	psi-mi:“MI:0915”(physical association)	0.570
NCK1	ASAP2	psi-mi:“MI:0915”(physical association)	0.560
NCK1	FYB1	psi-mi:“MI:0915”(physical association)	0.560
GHR	NCK1	psi-mi:“MI:0915”(physical association)	0.540
NCK1	OLIG1	psi-mi:“MI:0915”(physical association)	0.490
PIK3R3	NCK1	psi-mi:“MI:0915”(physical association)	0.490
NCK1	SH2D1A	psi-mi:“MI:0915”(physical association)	0.490
OLIG1	NCK1	psi-mi:“MI:0915”(physical association)	0.490
CAST	NCK1	psi-mi:“MI:0915”(physical association)	0.400
DLX4	NCK1	psi-mi:“MI:0915”(physical association)	0.400
BRPF3	NCK1	psi-mi:“MI:0915”(physical association)	0.400
NCK1	SYNJ2	psi-mi:“MI:0915”(physical association)	0.400
NCK1	CDC27	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (359): NCK1 (Two-hybrid), NCK1 (Affinity Capture-MS), NCK1 (Affinity Capture-MS), NCK1 (Affinity Capture-MS), NCK1 (Co-fractionation), OLIG1 (Two-hybrid), PIK3R3 (Two-hybrid), SH2D1A (Two-hybrid), EIF2S2 (Affinity Capture-Western), EIF2S2 (Reconstituted Complex), EIF2S2 (Two-hybrid), NCK1 (Proximity Label-MS), APBB2 (Affinity Capture-MS), WIPF1 (Affinity Capture-MS), TRRAP (Affinity Capture-MS)

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: A1CAL7, A1DEZ0, A2QGW1, A5DR93, A5E1V8, A6QTM4, A6ZR73, A7F1F4, A7TI28, B0Y3Z4, B2ANF9, B2VV00, B3LRN4, B5VHP4, B6HR44, B6QEE0, B8MD74, B8NEM4, B8R1V5, B9W8T5, C0S7Q7, C1GJ63, C4JLG3, C4QVD6, C4Y1G1, C4YDC4, C5DE38, C5DQY5, C5FH98, C5GIQ8, C5JGE5, C5MB30, C6HFQ7, C7GKW5, C7Z504, C9SA05, D1ZRK4, D4ARB8, D4DA58, D6PVB4

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
NCK1	up-regulates	WASL	binding
NCK1	“down-regulates activity”	ABL1	binding
NCKIPSD	unknown	NCK1	binding
ABL1	up-regulates	NCK1	phosphorylation
NCK1	up-regulates	PAK1	binding
CBLB	“up-regulates activity”	NCK1	binding
CD3E	“up-regulates activity”	NCK1	relocalization
CD3	“up-regulates activity”	NCK1	relocalization
CBL	“down-regulates quantity by destabilization”	NCK1	ubiquitination
EIF2AK2	“down-regulates activity”	NCK1	phosphorylation
EGFR	up-regulates	NCK1
PDGFRB	up-regulates	NCK1	binding
NCK1	“up-regulates activity”	PAK1	binding
EGFR	“up-regulates activity”	NCK1	binding
NCK1	up-regulates	SOS1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 123 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
Interleukin-3, Interleukin-5 and GM-CSF signaling	5	18.0×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1400 predictions. Top by Δscore:

Variant	Effect	Δscore
3:136927979:TACA:T	acceptor_loss	1.0000
3:136927982:A:AG	acceptor_gain	1.0000
3:136927982:A:T	acceptor_loss	1.0000
3:136927982:AGT:A	acceptor_gain	1.0000
3:136927983:G:GA	acceptor_gain	1.0000
3:136927983:GT:G	acceptor_gain	1.0000
3:136927983:GTG:G	acceptor_gain	1.0000
3:136927983:GTGC:G	acceptor_gain	1.0000
3:136927983:GTGCT:G	acceptor_gain	1.0000
3:136928224:TTAGG:T	donor_loss	1.0000
3:136928225:TAGG:T	donor_loss	1.0000
3:136928226:AGGTA:A	donor_loss	1.0000
3:136928227:GGTAA:G	donor_loss	1.0000
3:136928228:G:GG	donor_gain	1.0000
3:136928228:GTA:G	donor_loss	1.0000
3:136928229:T:A	donor_loss	1.0000
3:136931436:GAA:G	donor_gain	1.0000
3:136946293:TCGGT:T	donor_loss	1.0000
3:136946294:CGGTA:C	donor_loss	1.0000
3:136946295:GGTA:G	donor_loss	1.0000
3:136946296:G:GG	donor_gain	1.0000
3:136946297:T:TC	donor_loss	1.0000
3:136948257:A:AG	acceptor_gain	1.0000
3:136948258:G:GA	acceptor_gain	1.0000
3:136948258:GCCA:G	acceptor_gain	1.0000
3:136948258:GCCAA:G	acceptor_gain	1.0000
3:136863421:A:T	donor_gain	0.9900
3:136906078:ATAG:A	acceptor_gain	0.9900
3:136906078:ATAGG:A	acceptor_gain	0.9900
3:136927972:AT:A	acceptor_gain	0.9900

AlphaMissense

2493 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:136928027:C:A	A9D	1.000
3:136928032:T:C	F11L	1.000
3:136928034:T:A	F11L	1.000
3:136928034:T:G	F11L	1.000
3:136928063:T:C	L21S	1.000
3:136928087:T:C	L29S	1.000
3:136928113:T:A	W38R	1.000
3:136928113:T:C	W38R	1.000
3:136928115:G:C	W38C	1.000
3:136928115:G:T	W38C	1.000
3:136928116:T:A	W39R	1.000
3:136928116:T:C	W39R	1.000
3:136928118:G:C	W39C	1.000
3:136928118:G:T	W39C	1.000
3:136928123:T:A	V41D	1.000
3:136928126:G:C	R42P	1.000
3:136928146:G:C	G49R	1.000
3:136928147:G:A	G49D	1.000
3:136928147:G:T	G49V	1.000
3:136928153:T:A	V51E	1.000
3:136928155:C:A	P52T	1.000
3:136928155:C:T	P52S	1.000
3:136928156:C:A	P52H	1.000
3:136928163:C:A	N54K	1.000
3:136928163:C:G	N54K	1.000
3:136928164:T:G	Y55D	1.000
3:136928168:T:A	V56E	1.000
3:136945688:C:A	A111D	1.000
3:136945699:T:C	F115L	1.000
3:136945700:T:C	F115S	1.000

dbSNP variants (sampled 300 via entrez): RS1000042986 (3:136927231 C>G,T), RS1000057310 (3:136921715 A>G,T), RS1000102337 (3:136884377 G>A), RS1000108288 (3:136877310 A>G), RS1000159853 (3:136869041 C>T), RS1000193801 (3:136900247 C>T), RS1000246672 (3:136884067 C>G,T), RS1000309465 (3:136914373 C>A,G,T), RS1000359086 (3:136908184 A>G), RS1000385510 (3:136864631 T>C,G), RS1000403846 (3:136887577 T>C), RS1000411006 (3:136866010 T>A), RS1000429930 (3:136921400 G>T), RS1000475456 (3:136950929 T>C,G), RS1000532397 (3:136916168 C>A)

Disease associations

OMIM: gene MIM:600508 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002539_50	Schizophrenia	7.000000e-11
GCST002783_255	Body mass index	1.000000e-06
GCST002783_434	Body mass index	1.000000e-06
GCST002783_472	Body mass index	1.000000e-06
GCST004099_19	B-cell malignancies (chronic lymphocytic leukemia, Hodgkin lymphoma or multiple myeloma) (pleiotropy)	2.000000e-09
GCST004521_157	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST006803_84	Schizophrenia	4.000000e-12
GCST008062_65	Blood urea nitrogen levels	5.000000e-16
GCST90002393_254	Monocyte count	1.000000e-13
GCST90002401_130	Platelet distribution width	2.000000e-10
GCST90002402_328	Platelet count	2.000000e-16

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0005091	monocyte count
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4846 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases reaction, increases expression, decreases expression, increases activity	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Valproic Acid	decreases expression	2
Cyclosporine	increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	affects cotreatment, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	increases expression	1
K 7174	increases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
Irinotecan	decreases expression	1
Decitabine	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL832688	Binding	Displacement of PRP-1 peptide from human Nck kinase SH3 domain by fluorescence polarization	Identification and specificity studies of small-molecule ligands for SH3 protein domains. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1Y9	Abcam HeLa NCK1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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