CRKL

Summary

CRKL (CRK like proto-oncogene, adaptor protein, HGNC:2363) is a protein-coding gene on chromosome 22q11.21, encoding Crk-like protein (P46109). May mediate the transduction of intracellular signals. It is a selective cancer dependency (DepMap: 72.4% of cell lines).

This gene encodes a protein kinase containing SH2 and SH3 (src homology) domains which has been shown to activate the RAS and JUN kinase signaling pathways and transform fibroblasts in a RAS-dependent fashion. It is a substrate of the BCR-ABL tyrosine kinase, plays a role in fibroblast transformation by BCR-ABL, and may be oncogenic.

Source: NCBI Gene 1399 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (No Known Disease Relationship, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 57 total
• Phenotypes (HPO): 60
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 72.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005207

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2363
Approved symbol	CRKL
Name	CRK like proto-oncogene, adaptor protein
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000099942
Ensembl biotype	protein_coding
OMIM	602007
Entrez	1399

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 nonsense_mediated_decay

ENST00000354336, ENST00000411769, ENST00000894699

RefSeq mRNA: 1 — MANE Select: NM_005207 NM_005207

CCDS: CCDS13785

Canonical transcript exons

ENST00000354336 — 3 exons

Exon	Start	End
ENSE00000650961	20933779	20934244
ENSE00001426302	20917407	20918245
ENSE00001426758	20949711	20953747

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.8956 / max 261.4352, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191168	24.6303	1813
191167	16.6888	1793
191169	0.5265	298
191171	0.0499	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.98	gold quality
oocyte	CL:0000023	98.42	gold quality
ventricular zone	UBERON:0003053	96.38	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.72	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.57	gold quality
paraflocculus	UBERON:0005351	95.05	gold quality
medial globus pallidus	UBERON:0002477	94.79	gold quality
embryo	UBERON:0000922	94.75	gold quality
ganglionic eminence	UBERON:0004023	94.53	gold quality
amniotic fluid	UBERON:0000173	94.35	gold quality
cerebellar vermis	UBERON:0004720	94.15	gold quality
middle frontal gyrus	UBERON:0002702	94.06	gold quality
globus pallidus	UBERON:0001875	93.92	gold quality
frontal pole	UBERON:0002795	93.53	gold quality
gastrocnemius	UBERON:0001388	93.40	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.28	gold quality
muscle of leg	UBERON:0001383	93.13	gold quality
biceps brachii	UBERON:0001507	93.11	gold quality
muscle organ	UBERON:0001630	93.04	gold quality
vastus lateralis	UBERON:0001379	92.86	gold quality
quadriceps femoris	UBERON:0001377	92.81	gold quality
skeletal muscle tissue	UBERON:0001134	92.77	gold quality
deltoid	UBERON:0001476	92.62	gold quality
sperm	CL:0000019	92.56	gold quality
thymus	UBERON:0002370	92.56	gold quality
middle temporal gyrus	UBERON:0002771	92.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.03	gold quality
esophagus squamous epithelium	UBERON:0006920	92.00	gold quality
muscle tissue	UBERON:0002385	91.96	gold quality
postcentral gyrus	UBERON:0002581	91.95	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.67
E-ENAD-20	no	4247.15

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MMP9	Repression

miRNA regulators (miRDB)

214 targeting CRKL, 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-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-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 72.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines (PMID:12393632)
• directs ASAP1 to peripheral focal adhesions in platelets (PMID:12522101)
• CrkL plays a specific role in integrin-induced migration as a downstream mediator of Src. (PMID:12665586)
• Cbl-b plays a negative role in Crk-L-C3G-mediated Rap1 and LFA-1 activation in T cells. (PMID:12697763)
• Data suggest that members of the insulin receptor family activate Crk isoforms Crk-II and Crk-L in a differential manner. (PMID:15522217)
• CD21 activation triggered Cbl tyrosine phosphorylation, which interacts with SH2 domains of p85 subunit, SH2 domains of Crk-L and with tyrosine phosphorylated Syk kinase. CD21 activation triggers dissociation of Cbl-Vav complex. (PMID:16289966)
• Results suggest that the interaction of the cytoplasmic tail of CD34 with the shallow proline-rich motif-binding groove of Crk-L is essential for the function of CD34 in stem cell development. (PMID:16305332)
• By lysing primary hemopoietic cells at high pH, BCR-ABL1 protein-degradative activity was inhibited & association between BCR-ABL1 protein in complexes with adaptor proteins CBL, CRKL & GRB2 in primary chronic myeloid leukaemia material was demonstrated (PMID:16955467)
• in CRKL, an SH3 domain dimer formed through exchange of the first SH3 domain beta strand and suggest that partial unfolding of the SH3C is important for the relay of information in vivo (PMID:17161365)
• Crk L is a bona fide nuclear signaling protein because of its ability to bind tyrosine-phosphorylated STAT5 and act as a transcriptional coactivator. (PMID:17764157)
• Confocal laser scanning microscopy analysed the distribution and colocalization of CT10 regulator-like (CRKL) p210(BCR-ABL). CRKL-p210(BCR-ABL) foci were completely or partially associated, touching or separate in different regions of the same cell. (PMID:18059481)
• the Spanish Flu virus resembles avian influenza A viruses in its ability to recruit Crk/CrkL to modulate host cell signaling. (PMID:18165234)
• These findings suggest a novel MUC1-Src-CrkL-Rac1/Cdc42 signaling cascade following ICAM-1 ligation, through which MUC1 regulates cytoskeletal reorganization and directed cell motility during cell migration. (PMID:18403635)
• Results identify a mechanism by which the WAVE2 complex regulates T cell receptor signaling to Rap1 and integrin activation via Abl- and CrkL-C3G. (PMID:18809728)
• along with DOCK1, DOCK5 is an important mediator of CrkII/CrkL regulation of Caco-2 spreading and migration on collagen IV. (PMID:19004829)
• CRKL permits cells to bypass the strict need for adhesion in response to FGF8 through direct interaction with receptor. (PMID:19307307)
• an interaction between the regulatory subunit of PI3K, p85, and the adaptor protein CrkL is required for efficient NKG2D-mediated cellular cytotoxicity (PMID:19454690)
• Findings indicate that amplification and resultant overexpression of CRKL contribute to diverse oncogenic phenotypes in lung cancer. (PMID:19966867)
• 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)
• Lyn controls spatial activation of Rap1 by recruiting the CrkL-C3G protein complex to the leading edge (PMID:21628423)
• The molecular signaling set off by ERalpha and CrkL association may have a central role in pregnancy and cancer. (PMID:21700719)
• These results suggest that CRKL, but not MAPK1 is the target oncogene of the rare but recurrent amplification at 22q11.2 in laryngeal squamous cell carcinoma. (PMID:21896986)
• Stathmin and CrkL proteins may be involved in drug resistance of K562 cells to adriamycin. (PMID:22169288)
• BCR-ABL activity measured by 50% inhibitory concentration for imatinib, p-CrkL/CrkL ratio or p-CrkL ratio in CD34+ cells of patients with chronic myeloid leukemia does not predict treatment response (PMID:22233112)
• these results indicate that CRKL regulates HNSCC-cell growth, motility, and integrin-dependent cell adhesion, suggesting that CRKL plays a principal role in HNSCC tumorigenicity. (PMID:22244889)
• In silico three-dimensional modeling of apoptin, molecular docking experiments between apoptin model and the known structure of Bcr-Abl, and the 3D structures of SH2 domains of CrkL and Bcr-Abl, were performed. (PMID:22253690)
• study reveals a significant association between Crk protein expression with highly proliferative tumors and basal breast cancers of poor outcome; data highlight the physiological importance of Crk proteins in regulating growth of aggressive basal breast cancer cells (PMID:22569336)
• CRKL overexpression induces cell transformation. (PMID:22586683)
• These results suggested that CRKL protein is overexpressed in a subset of gastric cancers and is associated with CRKL amplification in gastric cancer. (PMID:22591714)
• Overexpression of CRKL in HBE and H1299 cell lines promoted cell proliferation by facilitating cell cycle progression. (PMID:22753141)
• we identified CRKL/YES as critical interrelated pathways necessary for rhabdomyosarcoma cell growth and survival and suggest a potential therapeutic role of SRC family kinase inhibition in the treatment of rhabdomyosarcoma. (PMID:23318429)
• High expression levels of the CRKL and CRKL-FLT1 pair strongly correlate with reduced disease-free and overall survival in HCC patient samples. (PMID:23397142)
• Overexpression of CRKL correlated with progression and malignant proliferation of human breast cancers. (PMID:23686806)
• Data show Src-inducible association of CrkL with procaspase-8 promotes cell migration. (PMID:23751956)
• SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain (PMID:23770091)
• Knock-down of CRKL in SGC-7901 cells induced a suppression of cell proliferation along with a significant arrest of cell cycle in G0/G1 phase. (PMID:24055140)
• CRKL may recruit NleH1 to a host kinase on which NleH1 performs its inhibitory function. (PMID:24145029)
• This is the first report to elucidate the novel function of NS1–binding protein collaborating with viral protein NS1 in modulation of host cell physiology. In addition, an alternative role of adaptor protein CRKL in association with NS1 and NS1-BP during influenza A virus infection is demonstrated. (PMID:24220336)
• CRKL is overexpressed in bladder cancer and regulates malignant cell growth and invasion. (PMID:24375195)
• results suggest that CRKL has the ability to regulate colon cancer malignancy and CRKL has the potential to serve as a diagnosis and prognosis marker and a therapy target of colon cancer (PMID:24389200)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	crkl	ENSDARG00000028699
mus_musculus	Crkl	ENSMUSG00000006134
rattus_norvegicus	Crkl	ENSRNOG00000001868
drosophila_melanogaster	Crk	FBGN0024811
caenorhabditis_elegans		WBGENE00000416

Paralogs (1): CRK (ENSG00000167193)

Protein

Protein identifiers

Crk-like protein — P46109 (reviewed: P46109)

All UniProt accessions (1): P46109

UniProt curated annotations — full annotation on UniProt →

Function. May mediate the transduction of intracellular signals.

Subunit / interactions. Interacts with tyrosine-phosphorylated EPOR and INPP5D/SHIP1. Interacts with DOCK2 and DOCK5 via its first SH3 domain. Interacts with phosphorylated CBLB and IRS4. Interacts with BCAR1/CAS and NEDD9/HEF1.

Similarity. Belongs to the CRK family.

RefSeq proteins (1): NP_005198* (*=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 (40 total): strand 24, helix 7, domain 3, modified residue 2, chain 1, turn 1, region of interest 1, mutagenesis site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
2BZY	X-RAY DIFFRACTION	2.5
2BZX	X-RAY DIFFRACTION	2.8
2DBK	SOLUTION NMR
2EO3	SOLUTION NMR
2LQN	SOLUTION NMR
2LQW	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46109-F1	69.65	0.01

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 (2): 127, 207

Mutagenesis-validated functional residues (1):

Position	Phenotype
160	abolishes interaction with dock5.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-170968	Frs2-mediated activation
R-HSA-186763	Downstream signal transduction
R-HSA-8875555	MET activates RAP1 and RAC1
R-HSA-8875656	MET receptor recycling
R-HSA-9027284	Erythropoietin activates RAS
R-HSA-912631	Regulation of signaling by CBL

MSigDB gene sets: 618 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_DENDRITE_DEVELOPMENT, GOBP_SINGLE_FERTILIZATION, MODULE_97, GOBP_HINDBRAIN_DEVELOPMENT, GCM_MAP4K4, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_CELL_CHEMOTAXIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (58): regulation of cell growth (GO:0001558), blood vessel development (GO:0001568), urogenital system development (GO:0001655), neuron migration (GO:0001764), B cell apoptotic process (GO:0001783), outflow tract morphogenesis (GO:0003151), lipid metabolic process (GO:0006629), enzyme-linked receptor protein signaling pathway (GO:0007167), JNK cascade (GO:0007254), Ras protein signal transduction (GO:0007265), spermatogenesis (GO:0007283), single fertilization (GO:0007338), positive regulation of cell population proliferation (GO:0008284), fibroblast growth factor receptor signaling pathway (GO:0008543), male gonad development (GO:0008584), anterior/posterior pattern specification (GO:0009952), negative regulation of gene expression (GO:0010629), dendrite development (GO:0016358), cell migration (GO:0016477), hippocampus development (GO:0021766), cerebral cortex development (GO:0021987), establishment of cell polarity (GO:0030010), regulation of cell adhesion mediated by integrin (GO:0033628), positive regulation of Rac protein signal transduction (GO:0035022), intracellular signal transduction (GO:0035556), helper T cell diapedesis (GO:0035685), reelin-mediated signaling pathway (GO:0038026), retinoic acid receptor signaling pathway (GO:0048384), thymus development (GO:0048538), regulation of dendrite development (GO:0050773), T cell receptor signaling pathway (GO:0050852), parathyroid gland development (GO:0060017), cell chemotaxis (GO:0060326), negative regulation of SMAD protein signal transduction (GO:0060392), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to xenobiotic stimulus (GO:0071466), cellular response to transforming growth factor beta stimulus (GO:0071560), endothelin receptor signaling pathway (GO:0086100), acetylcholine receptor signaling pathway (GO:0095500), postsynaptic specialization assembly (GO:0098698)

GO Molecular Function (8): phosphotyrosine residue binding (GO:0001784), RNA binding (GO:0003723), receptor tyrosine kinase binding (GO:0030971), signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), cadherin binding (GO:0045296), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515)

GO Cellular Component (7): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), neuromuscular junction (GO:0031594), protein-containing complex (GO:0032991), extrinsic component of postsynaptic membrane (GO:0098890), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Prolonged ERK activation events	1
Signaling by PDGF	1
MET promotes cell motility	1
Signaling by MET	1
Signaling by Erythropoietin	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
cellular anatomical structure	3
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
vasculature development	1
system development	1
renal system development	1
cell migration	1
generation of neurons	1
lymphocyte apoptotic process	1
heart morphogenesis	1
anatomical structure morphogenesis	1
primary metabolic process	1
cell surface receptor signaling pathway	1
MAPK cascade	1
small GTPase-mediated signal transduction	1
developmental process involved in reproduction	1
male gamete generation	1
fertilization	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
gonad development	1
development of primary male sexual characteristics	1
regionalization	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
neuron projection development	1
cell motility	1
pallium development	1
limbic system development	1
protein phosphorylated amino acid binding	1
nucleic acid binding	1
signaling receptor binding	1
protein tyrosine kinase binding	1
protein-macromolecule adaptor activity	1

Protein interactions and networks

STRING

1796 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRKL	RAPGEF1	Q13905	997
CRKL	CBL	P22681	993
CRKL	STAT5B	P51692	983
CRKL	STAT5A	P42229	976
CRKL	BCAR1	P56945	968
CRKL	PXN	P49023	939
CRKL	DOCK1	Q14185	878
CRKL	WIPF1	O43516	860
CRKL	ABL1	P00519	856
CRKL	SHC1	P29353	832
CRKL	WAS	P42768	815
CRKL	TBX1	O43435	812
CRKL	CRK	P46108	798
CRKL	GRB2	P29354	792
CRKL	PTPN11	Q06124	782

IntAct

243 interactions, top by confidence:

A	B	Type	Score
CRKL	CBL	psi-mi:“MI:0915”(physical association)	0.870
PIK3CB	PIK3R1	psi-mi:“MI:0914”(association)	0.840
GAB1	CRKL	psi-mi:“MI:0915”(physical association)	0.750
EGFR	CRKL	psi-mi:“MI:0915”(physical association)	0.750
CRKL	GAB1	psi-mi:“MI:2364”(proximity)	0.750
EGFR	CRKL	psi-mi:“MI:2364”(proximity)	0.750
ABL1	CRKL	psi-mi:“MI:0217”(phosphorylation reaction)	0.740
CRKL	CRKL	psi-mi:“MI:0407”(direct interaction)	0.720
RAPGEF1	CRKL	psi-mi:“MI:0914”(association)	0.720
CEP170	KIF2A	psi-mi:“MI:2364”(proximity)	0.650
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
NCKIPSD	GEMIN2	psi-mi:“MI:0914”(association)	0.640
Kcnma1	CRKL	psi-mi:“MI:0407”(direct interaction)	0.640
CRKL	Kcnma1	psi-mi:“MI:0915”(physical association)	0.640
CRKL	CBLB	psi-mi:“MI:0915”(physical association)	0.620
FYB1	NCK2	psi-mi:“MI:0914”(association)	0.620
CRKL	CBLB	psi-mi:“MI:0914”(association)	0.620
CRKL	PDGFRA	psi-mi:“MI:2364”(proximity)	0.570
YES1	CRKL	psi-mi:“MI:0915”(physical association)	0.560
CRKL	PSMC6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (414): CRKL (Affinity Capture-MS), CRKL (Affinity Capture-RNA), CRKL (Affinity Capture-RNA), CBL (Reconstituted Complex), CRKL (Affinity Capture-MS), RAPGEF1 (Affinity Capture-Western), CRKL (Two-hybrid), CRKL (Co-fractionation), CRKL (Co-fractionation), CRKL (Co-fractionation), HIP1R (Co-fractionation), HNRNPH2 (Co-fractionation), PDCD6 (Co-fractionation), CRKL (Affinity Capture-MS), CRKL (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: A6NKC9, A6X942, G5ECJ6, O08908, O88834, P03949, P46109, P47941, Q00655, Q08012, Q08CX2, Q56A36, Q5SQS7, Q5U2U2, Q6AYC8, Q6VYH9, Q6YKA8, Q8BI17, Q8UUU2, Q96JZ2, Q9D7V1, Q9H788, Q9NP31, Q9QXK9, A0JNB0, A1A5H8, A1Y2K1, A6ZR73, A7A261, A8XI74, B0BNA1, B1V8A0, B3LRN4, B5VHP4, C7GKW5, D8PSG0, E7A253, E7KBW4, E7KMS3, E7LTJ6

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ABL1	down-regulates	CRKL
CRKL	“up-regulates activity”	PIK3CB	binding
BCR-ABL	up-regulates	CRKL	phosphorylation
CRKL	up-regulates	MAP4K1	binding
DOK7	“up-regulates activity”	CRKL	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 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
Tie2 Signaling	6	30.8×	3e-06
Constitutive Signaling by EGFRvIII	5	30.5×	2e-05
Regulation of signaling by CBL	7	29.7×	7e-07
Downstream signal transduction	9	29.3×	9e-09
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	24.4×	7e-05
Signaling by CSF1 (M-CSF) in myeloid cells	7	20.7×	3e-06
Interleukin-3, Interleukin-5 and GM-CSF signaling	7	19.0×	6e-06
RET signaling	8	17.8×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	7	20.6×	1e-05
insulin-like growth factor receptor signaling pathway	5	17.3×	1e-03
ephrin receptor signaling pathway	7	16.8×	4e-05
cell surface receptor protein tyrosine kinase signaling pathway	13	15.8×	2e-09
epidermal growth factor receptor signaling pathway	9	15.6×	3e-06
cellular response to reactive oxygen species	5	14.4×	2e-03
B cell receptor signaling pathway	5	14.0×	2e-03
insulin receptor signaling pathway	8	12.4×	5e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	22
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

637 predictions. Top by Δscore:

Variant	Effect	Δscore
22:20918244:AGGT:A	donor_loss	1.0000
22:20918245:GG:G	donor_loss	1.0000
22:20918246:GT:G	donor_loss	1.0000
22:20918247:T:G	donor_loss	1.0000
22:20933775:TAA:T	acceptor_loss	1.0000
22:20933776:AAG:A	acceptor_gain	1.0000
22:20933777:A:AG	acceptor_loss	1.0000
22:20933777:A:G	acceptor_gain	1.0000
22:20933778:G:A	acceptor_gain	1.0000
22:20933778:GG:G	acceptor_loss	1.0000
22:20933778:GGT:G	acceptor_gain	1.0000
22:20933774:TTAAG:T	acceptor_gain	0.9900
22:20933775:TAAG:T	acceptor_gain	0.9900
22:20933776:A:AG	acceptor_gain	0.9900
22:20933776:AAGG:A	acceptor_gain	0.9900
22:20933777:AG:A	acceptor_gain	0.9900
22:20933777:AGG:A	acceptor_gain	0.9900
22:20933778:G:GT	acceptor_gain	0.9900
22:20933778:GGTAT:G	acceptor_gain	0.9900
22:20934240:TAGAG:T	donor_loss	0.9900
22:20934241:AGAG:A	donor_loss	0.9900
22:20934243:AG:A	donor_loss	0.9900
22:20934244:GG:G	donor_loss	0.9900
22:20934245:G:GA	donor_loss	0.9900
22:20934246:T:A	donor_loss	0.9900
22:20938340:T:A	acceptor_gain	0.9900
22:20949706:TACAG:T	acceptor_loss	0.9900
22:20949709:A:AC	acceptor_loss	0.9900
22:20949709:AGGTT:A	acceptor_gain	0.9900
22:20949710:G:A	acceptor_loss	0.9900

AlphaMissense

1976 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:20917974:T:A	W14R	1.000
22:20917974:T:C	W14R	1.000
22:20917995:C:A	R21S	1.000
22:20917995:C:T	R21C	1.000
22:20918017:T:C	L28P	1.000
22:20918034:G:C	G34R	1.000
22:20918035:G:A	G34D	1.000
22:20918035:G:T	G34V	1.000
22:20918040:T:A	F36I	1.000
22:20918040:T:C	F36L	1.000
22:20918041:T:C	F36S	1.000
22:20918041:T:G	F36C	1.000
22:20918042:C:A	F36L	1.000
22:20918042:C:G	F36L	1.000
22:20918044:T:C	L37P	1.000
22:20918047:T:A	V38D	1.000
22:20918049:C:A	R39S	1.000
22:20918050:G:C	R39P	1.000
22:20918056:C:T	S41F	1.000
22:20918079:G:A	V49M	1.000
22:20918080:T:A	V49E	1.000
22:20918083:T:A	L50Q	1.000
22:20918083:T:C	L50P	1.000
22:20918083:T:G	L50R	1.000
22:20918085:T:C	S51P	1.000
22:20918086:C:G	S51W	1.000
22:20918089:T:A	V52E	1.000
22:20918107:T:A	V58D	1.000
22:20918109:T:C	S59P	1.000
22:20918112:C:G	H60D	1.000

dbSNP variants (sampled 300 via entrez): RS1000008362 (22:20938698 T>C,G), RS1000039785 (22:20951082 T>G), RS1000065805 (22:20944975 C>T), RS1000164249 (22:20932543 T>C), RS1000177821 (22:20934730 G>A,C), RS1000286778 (22:20929224 G>A), RS1000400125 (22:20926351 A>G), RS1000423756 (22:20929377 G>C), RS1000608829 (22:20940032 C>T), RS1000701962 (22:20928163 A>C), RS1000914638 (22:20933312 G>C), RS1001087351 (22:20917305 A>G), RS1001110504 (22:20939250 T>C,G), RS1001175294 (22:20950100 A>C,T), RS1001318859 (22:20945215 G>A)

Disease associations

OMIM: gene MIM:602007 | disease phenotypes:

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	No Known Disease Relationship	UD

Mondo (0):

Orphanet (0):

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000010	Recurrent urinary tract infections
HP:0000023	Inguinal hernia
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000307	Pointed chin
HP:0000319	Smooth philtrum
HP:0000324	Facial asymmetry
HP:0000363	Abnormal earlobe morphology
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000430	Underdeveloped nasal alae
HP:0000453	Choanal atresia
HP:0000490	Deeply set eye
HP:0000581	Blepharophimosis
HP:0000657	Oculomotor apraxia
HP:0000716	Depression
HP:0000722	Compulsive behaviors
HP:0001166	Arachnodactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001382	Joint hypermobility
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001622	Premature birth
HP:0001629	Ventricular septal defect

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004616_174	Platelet distribution width	7.000000e-13
GCST90002395_616	Mean platelet volume	6.000000e-09
GCST90002401_344	Platelet distribution width	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291558 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.11	Kd	77.94	nM	CHEMBL3752910
7.07	ED50	84.33	nM	CHEMBL3752910
5.03	Kd	9417	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 19 total; 2 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148138: Binding affinity to human CRKL incubated for 45 mins by Kinobead based pull down assay	kd	0.0779	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148138: Binding affinity to human CRKL incubated for 45 mins by Kinobead based pull down assay	kd	9.4167	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Imatinib Mesylate	decreases reaction, increases phosphorylation, decreases phosphorylation, affects cotreatment	4
Dasatinib	affects cotreatment, decreases phosphorylation, decreases reaction, increases phosphorylation	3
Estradiol	affects expression, affects binding, increases expression	3
bisphenol A	increases expression	2
nilotinib	decreases reaction, increases phosphorylation, affects cotreatment, decreases phosphorylation	2
ponatinib	decreases reaction, increases phosphorylation, decreases phosphorylation	2
Smoke	increases abundance, increases expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cadmium Chloride	decreases expression	2
FR900359	increases phosphorylation	1
sodium arsenate	decreases expression	1
trichostatin A	affects expression, decreases reaction	1
cinnamaldehyde	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases expression	1
microcystin RR	increases expression	1
di-n-butylphosphoric acid	affects expression	1
alvocidib	affects cotreatment, decreases phosphorylation	1
chloropicrin	decreases expression	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
quinocetone	decreases expression, increases expression	1
ON 01910	affects cotreatment, decreases phosphorylation	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Bortezomib	affects cotreatment, decreases phosphorylation	1
Sorafenib	affects cotreatment, decreases reaction, increases phosphorylation, decreases phosphorylation	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5241032	Binding	Inhibition of CRKL phosphorylation in human K562 cells at 2.5 to 10 uM by Western blot analysis	Synthesis and biological evaluation of novel aromatic amide derivatives as potential BCR-ABL inhibitors. — Bioorg Med Chem Lett

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_B1PA	Abcam HeLa CRKL KO	Cancer cell line	Female
CVCL_D8JB	Ubigene HCT 116 CRKL KO	Cancer cell line	Male
CVCL_D9CD	Ubigene HEK293 CRKL KO	Transformed cell line	Female
CVCL_E0B0	Ubigene HeLa CRKL KO	Cancer cell line	Female

Clinical trials (associated diseases)

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