CRK

Summary

CRK (CRK proto-oncogene, adaptor protein, HGNC:2362) is a protein-coding gene on chromosome 17p13.3, encoding Adapter molecule crk (P46108). Involved in cell branching and adhesion mediated by BCAR1-CRK-RAPGEF1 signaling and activation of RAP1. It is a selective cancer dependency (DepMap: 11.8% of cell lines).

This gene encodes a member of an adapter protein family that binds to several tyrosine-phosphorylated proteins. The product of this gene has several SH2 and SH3 domains (src-homology domains) and is involved in several signaling pathways, recruiting cytoplasmic proteins in the vicinity of tyrosine kinase through SH2-phosphotyrosine interaction. The N-terminal SH2 domain of this protein functions as a positive regulator of transformation whereas the C-terminal SH3 domain functions as a negative regulator of transformation. Two alternative transcripts encoding different isoforms with distinct biological activity have been described.

Source: NCBI Gene 1398 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 62 total — 11 pathogenic, 2 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 11.8% of screened cell lines
• MANE Select transcript: NM_016823

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2362
Approved symbol	CRK
Name	CRK proto-oncogene, adaptor protein
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167193
Ensembl biotype	protein_coding
OMIM	164762
Entrez	1398

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000300574, ENST00000398970, ENST00000572145, ENST00000574295

RefSeq mRNA: 2 — MANE Select: NM_016823 NM_005206, NM_016823

CCDS: CCDS11002, CCDS45561

Canonical transcript exons

ENST00000300574 — 3 exons

Exon	Start	End
ENSE00001199117	1436620	1437155
ENSE00001199129	1455877	1456232
ENSE00003583603	1420693	1423650

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 97.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.0952 / max 609.8672, expressed in 1813 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163706	33.0767	1813
163707	0.0185	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.79	gold quality
oocyte	CL:0000023	97.08	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.98	gold quality
colonic mucosa	UBERON:0000317	95.70	gold quality
pericardium	UBERON:0002407	95.46	gold quality
lower lobe of lung	UBERON:0008949	95.38	gold quality
cortical plate	UBERON:0005343	94.96	gold quality
trigeminal ganglion	UBERON:0001675	94.91	gold quality
pons	UBERON:0000988	94.71	gold quality
corpus epididymis	UBERON:0004359	94.64	gold quality
body of tongue	UBERON:0011876	94.34	gold quality
calcaneal tendon	UBERON:0003701	94.33	gold quality
seminal vesicle	UBERON:0000998	94.26	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.21	gold quality
pharyngeal mucosa	UBERON:0000355	94.11	gold quality
vena cava	UBERON:0004087	94.08	gold quality
dorsal root ganglion	UBERON:0000044	94.01	gold quality
parietal pleura	UBERON:0002400	93.95	gold quality
heart right ventricle	UBERON:0002080	93.89	gold quality
tongue	UBERON:0001723	93.86	gold quality
esophagus squamous epithelium	UBERON:0006920	93.83	gold quality
visceral pleura	UBERON:0002401	93.73	gold quality
saphenous vein	UBERON:0007318	93.72	gold quality
superior surface of tongue	UBERON:0007371	93.63	gold quality
placenta	UBERON:0001987	93.60	gold quality
nipple	UBERON:0002030	93.59	gold quality
synovial joint	UBERON:0002217	93.58	gold quality
pleura	UBERON:0000977	93.54	gold quality
superior vestibular nucleus	UBERON:0007227	93.47	gold quality
smooth muscle tissue	UBERON:0001135	93.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

86 targeting CRK, 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-6867-5P	100.00	82.21	3464
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-499A-5P	99.98	70.79	1323
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Molecular and immunohistochemical analysis of signaling adaptor protein Crk in human cancers (PMID:11911970)
• determined the NMR solution structure of the ternary complex of the Abl SH3 domain with the Crk SH2 domain bound to a Crk pY221 phosphopeptide (PMID:12384576)
• Crk plays a critical role in Rac1-induced membrane ruffling and Rap1-mediated nascent focal complex stabilization contributing to ephrin-B1-induced human aortic endothelial cells migration (PMID:12475948)
• Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration in a metastatic prostate cancer cell line. (PMID:12738793)
• CRK is ADP ribosylated by Pseudomonas aeruginosa ExoT, demonstrating how ADP-ribosylation of Crk-I may be responsible for the anti-phagocytosis phenotype elicited by ExoT in mammalian cells (PMID:12807879)
• c-Src phosphorylates the receptor KIT, thereby creating docking sites for SH2 domain containing proteins, leading to recruitment of Crk to the receptor. (PMID:12878163)
• This study provides the first quantitative analysis of discrete CRKI and CRKII protein isoforms in human lung tumors and provides evidence that the C-CRK proto-oncogene may foment a more aggressive phenotype in lung cancers. (PMID:12970743)
• Nck and Crk mediate distinct VEGF-induced signaling pathways that serve overlapping functions in cell migration. (PMID:15051508)
• a major role for a Crk-cortactin complex in actin polymerization downstream of tyrosine kinase signaling (PMID:15263018)
• Crk may be involved in regulation of cell motility by a hyaluronic acid-dependent mechanism through an association with ERMs (PMID:15326184)
• Data suggest that members of the insulin receptor family activate Crk isoforms Crk-II and Crk-L in a differential manner. (PMID:15522217)
• while N-terminal SH3 of CrkII promotes assembly between CrkII and DOCK180, the C-terminal SH3 of CrkII regulates the stability and turnover of the DOCK180/ELMO complex (PMID:15700267)
• Crk adaptor proteins as critical integrators of upstream signals for cell invasion and migration in human cancer cell lines and support a role for Crk in metastatic spread (PMID:15831672)
• A mechanism for how Crk-II functions in the transactivation of the Abl tyrosine kinase. (PMID:16158059)
• Helicobacter pylori CagA/human Crk signaling contributes to promotion of H. pylori-gastritis and to the generation of a tumor microenvironment (PMID:16275761)
• results suggest that biological functions attributed to the association of Zap70 with Vav after T cell activation may equally reflect the association of Zap70 with CrkII, and further support a regulatory role for CrkII in TCR-linked signal transduction (PMID:16339550)
• LOX regulates cell motility/migration through changes in actin filament polymerization, which involve the regulation of the p130(Cas)/Crk/DOCK180 (PMID:16440329)
• The SH2-SH3 adaptor protein Crk is an essential target of GIT2 inhibition. (PMID:16628223)
• We provide evidence that Crk adaptor protein is required for the sustained phosphorylation of c-Met-docking protein Grb2-associated binder 1 (Gab1) in response to HGF, leading to the enhanced cell motility of human synovial sarcoma cell lines. (PMID:16849525)
• CrkII-DOCK180 is also responsible, at least in part, for the effects of Fcgamma receptors implies (PMID:17308335)
• Ab1 functions as a negative regulator of Met-induced cell motility via phosphorylation of the adaptor protin CRKII. (PMID:17399949)
• Study shows that CrkII is also important for the Helicobacter pylori CagA protein-induced signalling. (PMID:17428306)
• Signif. percentage of the Crk II partitions in the nucleus in mammalian cells, in complexes with DOCK180, Wee1, and Abl. It suggest that nuclear location of Crk II antagonizes its cytosk. functions and assign a proapoptotic role to the nuclear Crk II. (PMID:17764157)
• These results suggest that Crk is required for early attachment to laminin, cell motility, and growth of glioblastoma cell line KMG4. (PMID:17825249)
• CrkII SH3C domain engages a cellular ligand that regulates PI 3 kinase activity and host cell surface rearrangements (PMID:17848169)
• the Spanish Flu virus resembles avian influenza A viruses in its ability to recruit Crk/CrkL to modulate host cell signaling. (PMID:18165234)
• Over-expression of miR126 in a lung cancer cell line resulted in a decrease in Crk protein without any alteration in the associated mRNA. (PMID:18602365)
• uPAR cooperates with integrin complexes containing beta(3) integrin to drive formation of the p130Cas-CrkII signaling complex and activation of Rac, resulting in a Rac-driven elongated-mesenchymal morphology, cell motility, and invasion. (PMID:18725541)
• Rap1 as another downstream target of the Abl-CrkII signaling module and show that Abl-CrkII collaborates with Rho-ROCK1 to stimulate cell retraction. (PMID:19001122)
• along with DOCK1, DOCK5 is an important mediator of CrkII/CrkL regulation of Caco-2 spreading and migration on collagen IV. (PMID:19004829)
• The beta-sheet of the N-terminal Src homology 3 (nSH3) domain adopts at least two folded conformations and that the protein is likely not a random coil when denatured by guanidine hydrochloride. (PMID:19351132)
• is a signal transducing adaptor molecule that links tyrosine kinase and low-molecular weight G protein and plays role in various life phenomena. (PMID:19522292)
• Depletion of Crk by RNA interference markedly inhibited proliferation of the synovial sarcoma cell lines HS-SYII, SYO-1, and Fuji as well as prevented anchorage-independent growth. (PMID:19737974)
• Silencing of CRK-I/II increased endothelial cell migration. (PMID:19760510)
• These results imply that binding capacity of influenza A virus NS1 to CRK/CRKL has evolved in virus strains that over-induce the antiviral acting JNK-ATF2 signalling module and helps to suppress the detrimental apoptosis promoting action of this pathway. (PMID:20088952)
• signal transfer of Crk/Dock180/Rac1 is implicated in actin cytoskeleton reorganization and thus in the cell proliferation, motility, invasion, and of human ovarian cancer cell line SKOV3. (PMID:20237902)
• SOS1 is essential for CrkI-induced fibroblast transformation, and also reveal a surprising negative role for Abl kinases in Crk transformation. (PMID:20729917)
• differential binding selectivity of Crk and CrkL to their downstream partners Dock 180 and C3G was demonstrated in ovarian cancer cell line SKOV3 through coimmunoprecipitation (PMID:21319228)
• CRKII increases migration and invasive potential in oral squamous cell carcinoma (PMID:21339045)
• positive regulatory role resulting from tyrosine phosphorylation of Crk, and identify a novel mechanism by which an adaptor protein activates a non-receptor tyrosine kinase by SH2 domain displacement (PMID:21602891)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	crk	ENSDARG00000055635
mus_musculus	Crk	ENSMUSG00000017776
rattus_norvegicus	Crk	ENSRNOG00000025792
drosophila_melanogaster	Crk	FBGN0024811
caenorhabditis_elegans		WBGENE00000416

Paralogs (1): CRKL (ENSG00000099942)

Protein

Protein identifiers

Adapter molecule crk — P46108 (reviewed: P46108)

Alternative names: Proto-oncogene c-Crk, p38

All UniProt accessions (5): A0A0S2Z3K9, A0A0S2Z3Q4, P46108, I3L297, L7RT18

UniProt curated annotations — full annotation on UniProt →

Function. Involved in cell branching and adhesion mediated by BCAR1-CRK-RAPGEF1 signaling and activation of RAP1. Regulates cell adhesion, spreading and migration. Mediates attachment-induced MAPK8 activation, membrane ruffling and cell motility in a Rac-dependent manner. Involved in phagocytosis of apoptotic cells and cell motility via its interaction with DOCK1 and DOCK4. May regulate the EFNA5-EPHA3 signaling.

Subunit / interactions. Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK. Within the complex, interacts with SH2D3C (via C-terminus), and BCAR1/CAS. Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases. Interacts with ABL1, C3G, DOCK3, DOCK5, MAP4K1, MAPK8 and SOS via its first SH3 domain. Interacts (via SH2 domain) with BCAR1, CBL, CBLB, PXN, IRS4 and GAB1 upon stimulus-induced tyrosine phosphorylation. Interacts (via SH2 domain) with several tyrosine-phosphorylated growth factor receptors such as EGFR and INSR. Interacts with FLT1 (tyrosine-phosphorylated). Interacts with DOCK1 and DOCK4. Interacts with SHB. Interacts with PEAK1. Interacts with FASLG. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and p130cas/BCAR1. Interacts (via SH2 domain) with the ‘Tyr-9’ phosphorylated form of PDPK1. Interacts with CBLC. Interacts (via SH2 domain) with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts with EPHA3 (phosphorylated); upon activation of EPHA3 by the ligand EFNA5 and EPHA3 tyrosine kinase activity-dependent and mediates EFNA5-EPHA3 signaling through RHOA GTPase activation. Interacts with KIT. Interacts with PEAK3; the interaction requires PEAK3 homodimerization.

Subcellular location. Cytoplasm. Cell membrane.

Post-translational modifications. Phosphorylated on Tyr-221 upon cell adhesion. Results in the negative regulation of the association with SH2- and SH3-binding partners, possibly by the formation of an intramolecular interaction of phosphorylated Tyr-221 with the SH2 domain. This leads finally to the down-regulation of the Crk signaling pathway. Isoform Crk-II: Phosphorylated by KIT. Proline isomerization at Pro-237 by PPIA acts as a switch between two conformations: an autoinhibitory conformation in the cis form, where the tandem SH3 domains interact intramolecularly, and an activated conformation in the trans form.

Domain organisation. The C-terminal SH3 domain function as a negative modulator for transformation and the N-terminal SH3 domain appears to function as a positive regulator for transformation. The SH2 domain mediates interaction with tyrosine phosphorylated proteins. Mediates interaction with SHB.

Similarity. Belongs to the CRK family.

Isoforms (2)

UniProt ID	Names	Canonical?
P46108-1	Crk-II	yes
P46108-2	Crk-I

RefSeq proteins (2): NP_005197, NP_058431* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001452	SH3_domain	Domain
IPR035457	CRK_SH3_N	Domain
IPR035458	CRK_SH3_C	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051184	Tyrosine-phos_adapter	Family

Pfam: PF00017, PF00018, PF07653

UniProt features (63 total): strand 29, modified residue 10, helix 5, mutagenesis site 4, domain 3, sequence conflict 3, splice variant 2, region of interest 2, initiator methionine 1, chain 1, turn 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
5UL6	X-RAY DIFFRACTION	1.45
6ATV	X-RAY DIFFRACTION	1.75
1JU5	SOLUTION NMR
2DVJ	SOLUTION NMR
2EYV	SOLUTION NMR
2EYW	SOLUTION NMR
2EYX	SOLUTION NMR
2EYY	SOLUTION NMR
2EYZ	SOLUTION NMR
2MS4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46108-F1	71.09	0.02

Functional residue map

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

Catalytic / active sites (1): 237 (proline switch)

Post-translational modifications (10): 40, 41, 74, 83, 108, 125, 221, 239, 194, 2

Mutagenesis-validated functional residues (4):

Position	Phenotype
150	abolishes interaction with dock1.
169	abolishes interaction with peak3.
169	abolishes interaction with dock5. abolishes rap1 activation.
275	no effect on interaction with peak3.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-170984	ARMS-mediated activation
R-HSA-186763	Downstream signal transduction
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-372708	p130Cas linkage to MAPK signaling for integrins
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-8849471	PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases
R-HSA-8875555	MET activates RAP1 and RAC1
R-HSA-8875656	MET receptor recycling
R-HSA-912631	Regulation of signaling by CBL
R-HSA-9664422	FCGR3A-mediated phagocytosis

MSigDB gene sets: 471 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_DENDRITE_DEVELOPMENT, E2F_Q4, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_METENCEPHALON_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_WOUND_HEALING, TGCGCANK_UNKNOWN, GOBP_CELL_CHEMOTAXIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_SYNAPSE_ASSEMBLY, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (49): neuron migration (GO:0001764), response to yeast (GO:0001878), regulation of transcription by RNA polymerase II (GO:0006357), lipid metabolic process (GO:0006629), enzyme-linked receptor protein signaling pathway (GO:0007167), cell population proliferation (GO:0008283), regulation of cell shape (GO:0008360), regulation of signal transduction (GO:0009966), positive regulation of smooth muscle cell migration (GO:0014911), dendrite development (GO:0016358), cell migration (GO:0016477), Rac protein signal transduction (GO:0016601), hippocampus development (GO:0021766), cerebral cortex development (GO:0021987), establishment of cell polarity (GO:0030010), actin cytoskeleton organization (GO:0030036), positive regulation of cell growth (GO:0030307), regulation of actin cytoskeleton organization (GO:0032956), regulation of cell adhesion mediated by integrin (GO:0033628), positive regulation of Rac protein signal transduction (GO:0035022), helper T cell diapedesis (GO:0035685), response to hepatocyte growth factor (GO:0035728), reelin-mediated signaling pathway (GO:0038026), response to hydrogen peroxide (GO:0042542), regulation of GTPase activity (GO:0043087), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), positive regulation of JNK cascade (GO:0046330), ephrin receptor signaling pathway (GO:0048013), regulation of dendrite development (GO:0050773), cell chemotaxis (GO:0060326), negative regulation of wound healing (GO:0061045), response to cholecystokinin (GO:0061847), cellular response to transforming growth factor beta stimulus (GO:0071560), cellular response to nitric oxide (GO:0071732), protein localization to membrane (GO:0072657), postsynaptic specialization assembly (GO:0098698), cerebellar neuron development (GO:0098749), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), response to peptide (GO:1901652), regulation of intracellular signal transduction (GO:1902531)

GO Molecular Function (19): phosphotyrosine residue binding (GO:0001784), insulin-like growth factor receptor binding (GO:0005159), cytoskeletal protein binding (GO:0008092), SH3 domain binding (GO:0017124), kinase binding (GO:0019900), signaling receptor complex adaptor activity (GO:0030159), receptor tyrosine kinase binding (GO:0030971), ubiquitin protein ligase binding (GO:0031625), signaling adaptor activity (GO:0035591), SH2 domain binding (GO:0042169), protein phosphorylated amino acid binding (GO:0045309), ephrin receptor binding (GO:0046875), scaffold protein binding (GO:0097110), protein tyrosine kinase binding (GO:1990782), signaling receptor binding (GO:0005102), protein binding (GO:0005515), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), protein-macromolecule adaptor activity (GO:0030674)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), membrane (GO:0016020), neuromuscular junction (GO:0031594), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Prolonged ERK activation events	1
Signaling by PDGF	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
Integrin signaling	1
Signaling by VEGF	1
Signaling by PTK6	1
MET promotes cell motility	1
Signaling by MET	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
Leishmania phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	6
signaling receptor binding	4
anatomical structure development	3
cellular anatomical structure	3
pallium development	2
protein domain specific binding	2
cell migration	1
generation of neurons	1
response to fungus	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
primary metabolic process	1
cell surface receptor signaling pathway	1
cellular process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
smooth muscle cell migration	1
regulation of smooth muscle cell migration	1
positive regulation of cell migration	1
neuron projection development	1
cell motility	1
small GTPase-mediated signal transduction	1
limbic system development	1
establishment or maintenance of cell polarity	1
cytoskeleton organization	1
actin filament-based process	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
regulation of cell adhesion	1
cell adhesion mediated by integrin	1
Rac protein signal transduction	1

Protein interactions and networks

STRING

2372 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRK	RAPGEF1	Q13905	999
CRK	DOCK1	Q14185	999
CRK	BCAR1	P56945	998
CRK	PXN	P49023	995
CRK	SRC	P12931	995
CRK	CBL	P22681	992
CRK	FRS2	Q8WU20	972
CRK	ELMO1	Q92556	970
CRK	ELMO3	Q96BJ8	959
CRK	NCK1	P16333	956
CRK	ABL1	P00519	954
CRK	ELMO2	Q96JJ3	935
CRK	WDR35	Q9P2L0	926
CRK	PTK2	Q05397	899
CRK	FYN	P06241	878

IntAct

453 interactions, top by confidence:

A	B	Type	Score
CBL	CRK	psi-mi:“MI:0915”(physical association)	0.920
CRK	CBL	psi-mi:“MI:0915”(physical association)	0.920
BCAR1	CRK	psi-mi:“MI:0914”(association)	0.820
BCAR1	CRK	psi-mi:“MI:0915”(physical association)	0.820
RAPGEF1	CRK	psi-mi:“MI:0915”(physical association)	0.810
CRK	PPFIBP2	psi-mi:“MI:0915”(physical association)	0.800
USP53	CRK	psi-mi:“MI:0915”(physical association)	0.790
CRK	USP53	psi-mi:“MI:0915”(physical association)	0.790
CRK	PSMC6	psi-mi:“MI:0915”(physical association)	0.780
CRK	ABL2	psi-mi:“MI:0217”(phosphorylation reaction)	0.770
CRK	ASAP3	psi-mi:“MI:0915”(physical association)	0.770
ABL2	CRK	psi-mi:“MI:0915”(physical association)	0.770
CBLB	CRK	psi-mi:“MI:0915”(physical association)	0.710

BioGRID (616): SPRR2A (Reconstituted Complex), CRK (Biochemical Activity), CRK (Biochemical Activity), CRK (Reconstituted Complex), CRK (Reconstituted Complex), CRK (Biochemical Activity), CRK (Biochemical Activity), CRK (Biochemical Activity), CRK (Affinity Capture-MS), FAM154A (Two-hybrid), CRK (Two-hybrid), PLSCR1 (Two-hybrid), DPPA4 (Two-hybrid), CRK (Two-hybrid), PSMC6 (Two-hybrid)

ESM2 similar proteins: A8XI74, F1N9Y5, G5ECJ6, O15075, P08487, P08630, P10686, P16885, P19174, P24135, P24604, P35991, P42680, P43403, P43404, P43405, P46108, P46109, P47941, P48025, P51813, P53356, P54936, P87378, Q00655, Q04929, Q06187, Q22070, Q24145, Q45FX5, Q54Y55, Q5U2U2, Q62077, Q62422, Q63768, Q64010, Q64725, Q6P686, Q6TGW5, Q6XJU9

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

19 interactions.

A	Effect	B	Mechanism
DOK4	up-regulates	CRK	binding
EPHA3	up-regulates	CRK	binding
ABL2	down-regulates	CRK	phosphorylation
ABL1	“down-regulates activity”	CRK	phosphorylation
PDGFRA	up-regulates	CRK	binding
PDGFRB	up-regulates	CRK	binding
CRK	“up-regulates activity”	PTK2	phosphorylation
EGFR	“down-regulates activity”	CRK	phosphorylation
CRK	up-regulates	RAPGEF1	binding
CRK	up-regulates	CBL	binding
MAP2K6	up-regulates	CRK	phosphorylation
CRK	up-regulates	MAP4K1	binding
IGF1R	“down-regulates activity”	CRK	phosphorylation
DOK7	“up-regulates activity”	CRK	binding
CRK	“up-regulates activity”	MAP4K5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 141 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 signaling by CBL	5	27.3×	5e-04
Interleukin-3, Interleukin-5 and GM-CSF signaling	5	17.4×	3e-03
Signaling by SCF-KIT	5	13.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	2
Uncertain significance	39
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1340219	GRCh37/hg19 17p13.3(chr17:1193547-1403538)x3	Pathogenic
1340305	GRCh37/hg19 17p13.3(chr17:1176459-1570012)x3	Pathogenic
145986	GRCh38/hg38 17p13.3(chr17:1325785-1445161)x3	Pathogenic
2684828	GRCh37/hg19 17p13.3(chr17:1203617-1429687)x3	Pathogenic
443656	GRCh37/hg19 17p13.3(chr17:1263628-1483869)x1	Pathogenic
564385	GRCh37/hg19 17p13.3(chr17:1180644-1826928)x3	Pathogenic
57176	GRCh38/hg38 17p13.3(chr17:1368601-1589181)x3	Pathogenic
59560	GRCh38/hg38 17p13.3(chr17:1281181-1541624)x1	Pathogenic
625578	GRCh37/hg19 17p13.3-13.2(chr17:47546-6287620)	Pathogenic
815874	GRCh37/hg19 17p13.3(chr17:525-2221159)x1	Pathogenic
980146	GRCh37/hg19 17p13.3(chr17:998888-1457526)x3	Pathogenic
149182	GRCh38/hg38 17p13.3(chr17:1311837-1530439)x3	Likely pathogenic
152374	GRCh38/hg38 17p13.3(chr17:1373829-1525806)x1	Likely pathogenic

SpliceAI

826 predictions. Top by Δscore:

Variant	Effect	Δscore
17:1421249:A:C	acceptor_gain	0.9900
17:1436832:T:TA	donor_gain	0.9900
17:1436832:TCTCG:T	donor_gain	0.9900
17:1437153:CCC:C	acceptor_gain	0.9900
17:1437154:CCC:C	acceptor_gain	0.9900
17:1437155:CCTG:C	acceptor_loss	0.9900
17:1437156:C:CC	acceptor_gain	0.9900
17:1437157:T:A	acceptor_loss	0.9900
17:1455871:CCTCA:C	donor_loss	0.9900
17:1455872:CTCA:C	donor_loss	0.9900
17:1455874:CA:C	donor_loss	0.9900
17:1455875:ACC:A	donor_loss	0.9900
17:1455876:CCGGG:C	donor_gain	0.9900
17:1423516:G:C	donor_gain	0.9800
17:1436780:T:TA	donor_gain	0.9800
17:1436866:G:A	donor_gain	0.9800
17:1437151:CACCC:C	acceptor_gain	0.9800
17:1437152:ACCC:A	acceptor_gain	0.9800
17:1437153:CCCC:C	acceptor_gain	0.9800
17:1437154:CC:C	acceptor_gain	0.9800
17:1437155:CC:C	acceptor_gain	0.9800
17:1455875:A:AC	donor_gain	0.9800
17:1455876:C:CC	donor_gain	0.9800
17:1436791:T:TA	donor_gain	0.9700
17:1436857:C:A	donor_gain	0.9700
17:1455861:C:A	donor_gain	0.9600
17:1455870:C:A	donor_gain	0.9600
17:1436807:A:AC	donor_gain	0.9400
17:1436808:C:CC	donor_gain	0.9400
17:1447201:A:C	acceptor_gain	0.9200

AlphaMissense

1977 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:1423556:A:T	V291D	1.000
17:1423560:G:C	H290D	1.000
17:1423564:G:C	F288L	1.000
17:1423564:G:T	F288L	1.000
17:1423566:A:G	F288L	1.000
17:1423568:G:T	P287Q	1.000
17:1423569:G:T	P287T	1.000
17:1423570:G:C	F286L	1.000
17:1423570:G:T	F286L	1.000
17:1423571:A:C	F286C	1.000
17:1423571:A:G	F286S	1.000
17:1423572:A:G	F286L	1.000
17:1423577:C:T	G284D	1.000
17:1423578:C:G	G284R	1.000
17:1423598:C:T	G277E	1.000
17:1423599:C:A	G277W	1.000
17:1423599:C:G	G277R	1.000
17:1423599:C:T	G277R	1.000
17:1423605:A:G	W275R	1.000
17:1423605:A:T	W275R	1.000
17:1423610:C:A	G273V	1.000
17:1423610:C:T	G273D	1.000
17:1423611:C:G	G273R	1.000
17:1423631:A:T	V266D	1.000
17:1423637:A:T	V264E	1.000
17:1436624:A:G	L258S	1.000
17:1436630:A:C	L256W	1.000
17:1436630:A:G	L256S	1.000
17:1436633:G:T	A255D	1.000
17:1436634:C:G	A255P	1.000

dbSNP variants (sampled 300 via entrez): RS1000109630 (17:1434938 G>C,T), RS1000191302 (17:1448531 G>A), RS1000253683 (17:1445802 T>C,G), RS1000283127 (17:1446089 T>C), RS1000457943 (17:1433516 T>A,C), RS1000510504 (17:1429455 G>C), RS1000777839 (17:1424077 T>TTC,TTG), RS1000808256 (17:1445066 T>G), RS1000809463 (17:1441736 C>T), RS1000861102 (17:1444428 C>G), RS1000933719 (17:1449494 A>G), RS1001041085 (17:1454031 T>A), RS1001048381 (17:1431259 G>A,C), RS1001059317 (17:1439403 A>G), RS1001178167 (17:1441516 A>T)

Disease associations

OMIM: gene MIM:164762 | disease phenotypes: MIM:612576

GenCC curated gene-disease

Mondo (1): chromosome 17P13.3, telomeric, duplication syndrome (MONDO:0012944)

Orphanet (1): Tibial aplasia-ectrodactyly syndrome (Orphanet:3329)

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004279_6	Systolic blood pressure	3.000000e-08
GCST004613_50	Sum neutrophil eosinophil counts	2.000000e-10
GCST004614_55	Granulocyte count	5.000000e-10
GCST004620_98	Sum basophil neutrophil counts	2.000000e-09
GCST004626_138	Myeloid white cell count	3.000000e-11
GCST004629_148	Neutrophil count	2.000000e-09
GCST004632_50	Lymphocyte percentage of white cells	2.000000e-10
GCST006414_32	Atrial fibrillation	3.000000e-09
GCST007096_236	Pulse pressure	3.000000e-10
GCST007099_173	Systolic blood pressure	2.000000e-06
GCST007267_232	Systolic blood pressure	7.000000e-12
GCST007930_48	Medication use (agents acting on the renin-angiotensin system)	2.000000e-09
GCST007998_20	Intraocular pressure	1.000000e-13
GCST90002389_215	Lymphocyte percentage of white cells	2.000000e-10

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0005763	pulse pressure measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567245	Split-Hand-Foot Malformation With Long Bone Deficiency 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5005 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.05	Kd	9	nM	CHEMBL4281456
6.40	Kd	400	nM	CHEMBL4289336
5.72	Kd	1900	nM	CHEMBL4284876

PubChem BioAssay actives

4 with measured affinity, of 18 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-1-[(2S)-2-amino-3-hydroxypropanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	1412482: Binding affinity to recombinant human CRK-2 nSH3 domain (1 to 304 residues) expressed in Escherichia coli by tryptophan fluorescence quenching assay	kd	0.0090	uM
(3S)-3-amino-4-[[(2S)-4-amino-1-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(1S)-1-carboxy-2-(4-hydroxyphenyl)ethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-4-oxobutanoic acid	1412482: Binding affinity to recombinant human CRK-2 nSH3 domain (1 to 304 residues) expressed in Escherichia coli by tryptophan fluorescence quenching assay	kd	0.4000	uM
(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-1-[(2S)-4-methyl-2-[[(2S)-2-[[(2S)-1-[(2S)-1-[(2S)-pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]pentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	1412488: Binding affinity to human c-CRK N-terminal SH3 domain expressed in Escherichia coli BL21 (DE3) by tryptophan fluorescence quenching assay	kd	1.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	affects cotreatment, increases expression, increases methylation	2
Rotenone	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
pyrazolo(3,4-d)pyrimidine	affects expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pyrimidifen	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
asparanin A	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Antimycin A	decreases expression	1
Benzene	increases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cannabinoids	affects methylation, increases abundance	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1019916	Binding	Inhibition of GST-tagged human recombinant full length Crk SH2 domain expressed in Escherichia coli JBL21 binding to biotinylated phosphotyrosine-containing peptide by ELISA	Vidalenolone, a novel phenolic metabolite from the tropical red alga Vidalia sp. — J Nat Prod

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1P9	Abcam HeLa CRK KO	Cancer cell line	Female
CVCL_D8JA	Ubigene HCT 116 CRK KO	Cancer cell line	Male
CVCL_D9CC	Ubigene HEK293 CRK KO	Transformed cell line	Female
CVCL_E0AZ	Ubigene HeLa CRK KO	Cancer cell line	Female

Clinical trials (associated diseases)

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