EPHB2

Summary

EPHB2 (EPH receptor B2, HGNC:3393) is a protein-coding gene on chromosome 1p36.12, encoding Ephrin type-B receptor 2 (P29323). Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.

This gene encodes a member of the Eph receptor family of receptor tyrosine kinase transmembrane glycoproteins. These receptors are composed of an N-terminal glycosylated ligand-binding domain, a transmembrane region and an intracellular kinase domain. They bind ligands called ephrins and are involved in diverse cellular processes including motility, division, and differentiation. A distinguishing characteristic of Eph-ephrin signaling is that both receptors and ligands are competent to transduce a signaling cascade, resulting in bidirectional signaling. This protein belongs to a subgroup of the Eph receptors called EphB. Proteins of this subgroup are distinguished from other members of the family by sequence homology and preferential binding affinity for membrane-bound ephrin-B ligands. Allelic variants are associated with prostate and brain cancer susceptibility. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2048 — RefSeq curated summary.

At a glance

• Gene–disease (curated): bleeding disorder, platelet-type, 22 (Moderate, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 174 total — 2 pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes — 30 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_017449

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3393
Approved symbol	EPHB2
Name	EPH receptor B2
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Aliases	Hek5, Tyro5
Ensembl gene	ENSG00000133216
Ensembl biotype	protein_coding
OMIM	600997
Entrez	2048

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000374627, ENST00000374630, ENST00000374632, ENST00000400191, ENST00000465676, ENST00000490436, ENST00000544305

RefSeq mRNA: 4 — MANE Select: NM_017449 NM_001309192, NM_001309193, NM_004442, NM_017449

CCDS: CCDS229, CCDS230, CCDS81279

Canonical transcript exons

ENST00000374630 — 16 exons

Exon	Start	End
ENSE00000908693	22905987	22906109
ENSE00000908694	22906710	22906957
ENSE00000908697	22910382	22910575
ENSE00000908698	22912444	22912599
ENSE00000955704	22784392	22785076
ENSE00001066292	22781421	22781485
ENSE00001647153	22907953	22908168
ENSE00001769046	22909022	22909171
ENSE00001834713	22913462	22921500
ENSE00002231787	22710839	22711043
ENSE00003469744	22882359	22882483
ENSE00003543084	22864877	22865212
ENSE00003546360	22892884	22893046
ENSE00003566661	22896414	22896478
ENSE00003626755	22895472	22895580
ENSE00003646952	22863037	22863192

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 92.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.5041 / max 168.3972, expressed in 1507 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1330	20.5041	1507

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	92.52	gold quality
ventricular zone	UBERON:0003053	91.52	gold quality
cortical plate	UBERON:0005343	89.32	gold quality
rectum	UBERON:0001052	87.84	gold quality
mucosa of transverse colon	UBERON:0004991	87.58	gold quality
embryo	UBERON:0000922	87.27	gold quality
cartilage tissue	UBERON:0002418	86.99	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.10	gold quality
triceps brachii	UBERON:0001509	85.80	gold quality
colonic mucosa	UBERON:0000317	85.72	gold quality
gluteal muscle	UBERON:0002000	85.48	gold quality
olfactory bulb	UBERON:0002264	81.98	gold quality
buccal mucosa cell	CL:0002336	81.53	silver quality
tendon of biceps brachii	UBERON:0008188	81.53	gold quality
type B pancreatic cell	CL:0000169	81.19	gold quality
duodenum	UBERON:0002114	80.67	gold quality
islet of Langerhans	UBERON:0000006	80.14	gold quality
caecum	UBERON:0001153	80.03	gold quality
vermiform appendix	UBERON:0001154	79.65	gold quality
heart right ventricle	UBERON:0002080	79.62	gold quality
cervix squamous epithelium	UBERON:0006922	79.58	gold quality
transverse colon	UBERON:0001157	79.41	gold quality
vena cava	UBERON:0004087	78.14	gold quality
decidua	UBERON:0002450	76.92	gold quality
pericardium	UBERON:0002407	76.83	gold quality
periodontal ligament	UBERON:0008266	76.43	silver quality
small intestine	UBERON:0002108	76.36	gold quality
right ovary	UBERON:0002118	76.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.17	gold quality
penis	UBERON:0000989	76.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	13.16
E-ANND-3	yes	8.30

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOS	Activation

Upstream regulators (CollecTRI, top): AP1, BCLAF1, BTF3, CTNNB1, EGR1, ESR1, ESR2, EZH2, HNF4A, HTATIP2, JUN, LEF1, MYC, NFKB, REL, SP1, SP3, SP7, SPI1, TCF7, ZHX2

miRNA regulators (miRDB)

290 targeting EPHB2, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4682	100.00	68.89	1258
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-3163	100.00	77.23	8605
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 40)

• RYK, a catalytically inactive receptor tyrosine kinase, associates with EphB2 and EphB3 but does not interact with AF-6. (PMID:11956217)
• role of extracellular signal-regulated kinase (ERK) during the differentiation of human monoblastic U937 cells stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) (PMID:12063024)
• liganded to EFNB1 and EFNB2, expresssed in gastric cancer (PMID:12136247)
• Glioma migration and invasion are promoted by activation of EphB2 or inhibited by blocking EphB2. Dysregulation of EphB2 expression or function may underlie glioma invasion. (PMID:15126357)
• our findings suggest that mutational inactivation of EPHB2 may be important in the progression and metastasis of prostate cancer. (PMID:15300251)
• defined the expression patterns of human ephrinB2, EphB4, and EphB2 in normal vessels of neonates (i.e. umbilici) and adults and compared them with those in congenital venous malformations (PMID:15718372)
• analysis of EphB1, EphB2, and EphB4-binding peptides interaction with antagonists with ephrin-like affinity (PMID:15722342)
• loss of EphB expression represents a critical step in colorectal cancer progression (PMID:15973414)
• Deregulated EphB2 expression may play a role in several cancer types with loss of EphB2 expression serving as an indicator of the possible pathogenetic role of EphB2 signaling in the maintenance of tissue architecture of colon epithelium. (PMID:16166419)
• progressive loss of EphB2 expression seen in each critical step of colon carcinogenesis, including the onset of invasion, dedifferentiation and metastasis which are paralleled by adverse patient outcome (PMID:16272170)
• These results demonstrate that the MAPK ERK signaling pathway contributes to the p53-independent antiproliferative functions of p14ARF. Furthermore, they identify a new mechanism by which phosphorylation at serine 216 participates to Cdc25C inactivation. (PMID:16582626)
• analysis of germline EPHB2 alterations in patients with colorectal tumors (PMID:16740153)
• High EPHB2 mutation rate is associated with gastric tumors with microsatellite instability (PMID:16819508)
• novel link between EphB forward signaling and SDF-1-induced signaling demonstrates a mechanism for cooperative regulation of endothelial cell movement. (PMID:16840724)
• Notch signaling by induction of Dll1 was necessary & sufficient to regulate ephrin-B2 expression & induce ephrin-B2-dependent branching morphogenesis in human arterial EC. (PMID:17234965)
• Genetic or epigenetic alterations of the EPHB2 gene might be an uncommon event in the development or progression of gastric cancers. (PMID:17295683)
• In conclusion, alpha(2A)-adrenoreceptor activates ERK and Akt in intestinal cells by a common pathway which depends on PI3-kinase activation and results from EGF receptor transactivation. (PMID:17655843)
• A tumor suppressor role for EPHB2 in rare colorectal cancer cases; rare germline EPHB2 variants may contribute to a small fraction of hereditary colorectal cancer. (PMID:18682749)
• Overexpression of the EphA4 gene and reduced expression of the EphB2 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer. (PMID:18695888)
• MMP7 and MMP9-mediated cleavage of EphB2 is induced by receptor-ligand interactions at the cell surface and that this event triggers cell-repulsive responses (PMID:18713744)
• EphBR-ephrinB interactions lead to monocyte adhesion and transmigration through the vascular endothelium. (PMID:18957513)
• EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage. (PMID:19366806)
• results have confirmed that BRCA1, RASSF1, GSTP1 and EPHB2 promoter methylation was found in each prostate cancer sample (PMID:19454503)
• the ephrinB2/EphB4 axis is dysregulated in multiple myeloma, and its activation by EphB4-Fc inhibits myeloma growth and bone disease (PMID:19597185)
• peptide EphB2/CTF2 released to the cytosol by the gamma-secretase processing of EphB2 receptor, has tyrosine kinase activity, and directly phosphorylates the N-methyl-d-aspartate receptor (NMDAR) subunits in both cell lines and primary neuronal cultures (PMID:19661068)
• EphB2 enhances proliferation through a kinase-dependent pathway and inhibits migration independent of its kinase activity (PMID:19962662)
• The MAPK pathway is important in the pro-death action of EphB2, through ERK1/2 phosphorylation and inhibition of this pathway using PD98059 counters EphB2-driven cell death. (PMID:20046096)
• Ephrin-B2 is a potent regulator of endothelial cell behavior, and indicate that the control of cell migration and angiogenesis by ephrins might involve both receptor-dependent and receptor-independent activities. (PMID:20233847)
• Even a moderate level of EphB2 expression has effects on tumour cells which results in reduced migration and invasiveness and slows the growth of colonic tumour implants in an in vivo model. (PMID:20339854)
• Mutation in EphB2 gene is associated with colorectal adenocarcinoma (PMID:21161727)
• at least in the context of pancreatic carcinoma CFPAC-1 cells, EphB2 plays a tumor suppressor role in cell proliferation and apoptosis (PMID:21292437)
• EphB2 is an ephrin receptor and is up-regulated in invasive tumors but its role needs to be confirmed in further cases of Wilms tumors. (PMID:21387540)
• The present study reveals a novel function for EphA1 and EphB2 in the induction of autophagy, suggesting a tumor suppressor role for these proteins in colorectal cancer. (PMID:21503576)
• data suggest that genetic variation at the EphB2 locus may increase risk of sporadic prostate cancer risk in African American men. (PMID:21603658)
• EPHB2 interacts with EPHB6 in breast tumor cell lines (PMID:21737611)
• Define the transcriptional targets of the reverse signaling by EphB2 acting exclusively as a ligand in epidermal keratinocyte differentiation. (PMID:21809346)
• High Eph-B2 is associated with Waldenstrom’s macroglobulinemia. (PMID:22010211)
• PTPN14 has a role in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1 (PMID:22233626)
• EphB2 silencing increased tumor cell proliferation. (PMID:22310282)
• Data indicated for the first time that EphrinB2 and EphB4 expressions increase according to the histopathological grade and KPS score of glioma, and their expression levels are related to the progression-free survival of glioblastoma patients. (PMID:22374425)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ephb2b	ENSDARG00000021539
danio_rerio	ephb2a	ENSDARG00000037373
mus_musculus	Ephb2	ENSMUSG00000028664
rattus_norvegicus	Ephb2	ENSRNOG00000012531

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

Ephrin type-B receptor 2 — P29323 (reviewed: P29323)

Alternative names: Developmentally-regulated Eph-related tyrosine kinase, ELK-related tyrosine kinase, EPH tyrosine kinase 3, EPH-like kinase 5, Renal carcinoma antigen NY-REN-47, Tyrosine-protein kinase TYRO5, Tyrosine-protein kinase receptor EPH-3

All UniProt accessions (3): B1AKC9, P29323, Q6NVW1

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. In addition to axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor. May be involved in the regulation of platelet activation and blood coagulation.

Subunit / interactions. Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Interacts (via PDZ-binding motif) with GRIP1 and PICK1 (via PDZ domain). Interacts with ARHGEF15; mediates ARHGEF15 phosphorylation, ubiquitination and degradation by the proteasome. Interacts with AQP1; involved in endolymph production in the inner ear. Interacts with SPSB1 and SPSB4. The phosphorylated form interacts with RASA1 (via SH2 domain 1). Interacts with EFNA5. Interacts with SH2D3C.

Subcellular location. Cell membrane. Cell projection. Axon. Dendrite.

Tissue specificity. Brain, heart, lung, kidney, placenta, pancreas, liver and skeletal muscle. Preferentially expressed in fetal brain.

Post-translational modifications. Autophosphorylated; ligand binding stimulates autophosphorylation on tyrosine residues. Polyubiquitinated; ligand binding stimulates ubiquitination. Ubiquitinated by RNF186 at Lys-891, mainly through ‘Lys-27’-linked polyubiquitin chains. Ubiquitinated by CRL2(KLHDC2) E3 ligase complex. Ligand binding induces cleavage by matrix metalloproteinases (MMPs) such as MMP7/MMP9, producing an EphB2/N-terminal fragment (NTF) and a C-terminal long fragment (EphB2-LF). EphB2-LF is further cleaved by MMPs, producing EphB2/CTF1 which is further cleaved by the PS1/gamma-secretase producing EphB2/CTF2.

Disease relevance. Prostate cancer (PC) [MIM:176807] A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. The gene represented in this entry may be involved in disease pathogenesis. EPHB2 mutations have been found in a prostate cancer cell line derived from a brain metastasis. Bleeding disorder, platelet-type, 22 (BDPLT22) [MIM:618462] An autosomal recessive disorder characterized by increased bleeding tendency due to platelet dysfunction. Clinical features include epistaxis, hematomas, bleeding after minor injuries, and menorrhagia. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P29323-1	1, EPHB2v, Long	yes
P29323-2	2, Short
P29323-3	3

RefSeq proteins (4): NP_001296121, NP_001296122, NP_004433, NP_059145* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001090	EPH_LBD	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001426	Tyr_kinase_rcpt_V_CS	Conserved_site
IPR001660	SAM	Domain
IPR003961	FN3_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011641	Tyr-kin_ephrin_A/B_rcpt-like	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016257	EPH	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR027936	EPH_TM	Domain
IPR034238	EphB2_rcpt_lig-bd	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR050449	Ephrin_rcpt_TKs	Family

Pfam: PF00041, PF00536, PF01404, PF07699, PF07714, PF14575, PF25599

Enzyme classification (BRENDA):

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (101 total): strand 21, helix 21, sequence variant 11, sequence conflict 11, domain 5, glycosylation site 4, chain 3, splice variant 3, modified residue 2, compositionally biased region 2, binding site 2, site 2, disulfide bond 2, topological domain 2, mutagenesis site 2, turn 2, signal peptide 1, region of interest 1, short sequence motif 1, active site 1, cross-link 1, transmembrane region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8EBL	X-RAY DIFFRACTION	1.37
1B4F	X-RAY DIFFRACTION	1.95
1F0M	X-RAY DIFFRACTION	2.2
3ZFM	X-RAY DIFFRACTION	2.27
2QBX	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29323-F1	80.41	0.49

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 (3): 746 (proton acceptor); 535–536 (cleavage; by a metalloproteinase); 561–562 (cleavage; by gamma-secretase/ps1)

Ligand- & substrate-binding residues (2): 627–635; 653

Post-translational modifications (3): 984, 891, 983

Disulfide bonds (2): 62–184, 97–107

Glycosylation sites (4): 265, 336, 428, 482

Mutagenesis-validated functional residues (2):

Position	Phenotype
787	no loss of ubiquitination by rnf186.
891	complete loss of ubiquitination by rnf186.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-373760	L1CAM interactions
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-3928664	Ephrin signaling
R-HSA-3928665	EPH-ephrin mediated repulsion of cells

MSigDB gene sets: 649 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, E2F_Q4_01, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEURON_RECOGNITION, GOBP_COGNITION, MYOGENIN_Q6, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_WOUND_HEALING, MORF_MSH3

GO Biological Process (64): angiogenesis (GO:0001525), urogenital system development (GO:0001655), positive regulation of immunoglobulin production (GO:0002639), negative regulation of cell adhesion (GO:0007162), nervous system development (GO:0007399), axon guidance (GO:0007411), axonal fasciculation (GO:0007413), learning or memory (GO:0007611), learning (GO:0007612), positive regulation of gene expression (GO:0010628), phosphorylation (GO:0016310), peptidyl-tyrosine phosphorylation (GO:0018108), optic nerve morphogenesis (GO:0021631), hindbrain tangential cell migration (GO:0021934), central nervous system projection neuron axonogenesis (GO:0021952), corpus callosum development (GO:0022038), regulation of blood coagulation (GO:0030193), positive regulation of cell migration (GO:0030335), positive regulation of B cell proliferation (GO:0030890), retinal ganglion cell axon guidance (GO:0031290), positive regulation of synaptic plasticity (GO:0031915), positive regulation of tumor necrosis factor production (GO:0032760), B cell activation (GO:0042113), inner ear morphogenesis (GO:0042472), regulation of receptor signaling pathway via JAK-STAT (GO:0046425), negative regulation of Ras protein signal transduction (GO:0046580), ephrin receptor signaling pathway (GO:0048013), regulation of neuronal synaptic plasticity (GO:0048168), positive regulation of long-term neuronal synaptic plasticity (GO:0048170), camera-type eye morphogenesis (GO:0048593), negative regulation of axonogenesis (GO:0050771), regulation of body fluid levels (GO:0050878), regulation of filopodium assembly (GO:0051489), positive regulation of synapse assembly (GO:0051965), roof of mouth development (GO:0060021), dendritic spine development (GO:0060996), dendritic spine morphogenesis (GO:0060997), positive regulation of dendritic spine morphogenesis (GO:0061003), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to lipopolysaccharide (GO:0071222)

GO Molecular Function (16): amyloid-beta binding (GO:0001540), protein tyrosine kinase activity (GO:0004713), transmembrane-ephrin receptor activity (GO:0005005), signaling receptor binding (GO:0005102), ATP binding (GO:0005524), axon guidance receptor activity (GO:0008046), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), transmembrane receptor protein tyrosine kinase activity (GO:0004714), ephrin receptor activity (GO:0005003), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), signaling receptor activity (GO:0038023)

GO Cellular Component (16): extracellular region (GO:0005576), nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), presynaptic membrane (GO:0042734), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), postsynaptic membrane (GO:0045211), hippocampal mossy fiber to CA3 synapse (GO:0098686), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
EPH-Ephrin signaling	3
Axon guidance	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
system development	2
axon guidance	2
protein binding	2
binding	2
neuron projection	2
synaptic membrane	2
postsynapse	2
synapse	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
renal system development	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
axonogenesis	1
neuron projection guidance	1
neuron recognition	1
axon development	1
neuron projection fasciculation	1
behavior	1
cognition	1
learning or memory	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
phosphate-containing compound metabolic process	1
protein phosphorylation	1
peptidyl-tyrosine modification	1
optic nerve development	1
cranial nerve morphogenesis	1
cell migration in hindbrain	1
central nervous system neuron axonogenesis	1
telencephalon development	1
anatomical structure development	1
blood coagulation	1
regulation of response to external stimulus	1

Protein interactions and networks

STRING

2734 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPHB2	EFNB1	P98172	999
EPHB2	EFNB2	P52799	999
EPHB2	EFNA5	P52803	996
EPHB2	EFNB3	Q15768	995
EPHB2	TIAM1	Q13009	927
EPHB2	ITSN1	Q15811	912
EPHB2	EFNA1	P20827	870
EPHB2	EFNA3	P52797	832
EPHB2	EFNA4	P52798	831
EPHB2	ITSN2	Q9NZM3	795
EPHB2	EFNA2	O43921	793
EPHB2	EPHA4	P54764	792
EPHB2	CDC42	P21181	767
EPHB2	BFSP2	Q13515	710
EPHB2	PICK1	Q9NRD5	706

IntAct

58 interactions, top by confidence:

A	B	Type	Score
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
EPHB2	EFNB1	psi-mi:“MI:0407”(direct interaction)	0.690
EPHA4	EPHB2	psi-mi:“MI:0915”(physical association)	0.540
NUP153	EPHB2	psi-mi:“MI:0915”(physical association)	0.540
EPHB2	NUP153	psi-mi:“MI:0407”(direct interaction)	0.540
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
EPHA2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
EPHB2	MYCBP2	psi-mi:“MI:0914”(association)	0.530
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
CSF1R	EPHB2	psi-mi:“MI:0914”(association)	0.500
EPHA7	EPHB2	psi-mi:“MI:0915”(physical association)	0.500
CSF1R	EPHB2	psi-mi:“MI:0915”(physical association)	0.500
	EPHB2	psi-mi:“MI:0407”(direct interaction)	0.440
	EPHB2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
EPHA6	HGS	psi-mi:“MI:0914”(association)	0.420
TRIM54	EPHB2	psi-mi:“MI:0915”(physical association)	0.400
MTMR14	EPHB2	psi-mi:“MI:0915”(physical association)	0.370
AFDN	EPHB2	psi-mi:“MI:0915”(physical association)	0.370
	SNAP23	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
	SGK1	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (250): EPHB2 (Affinity Capture-MS), EPHB2 (Affinity Capture-MS), KDM4A (Co-fractionation), EPHB2 (Two-hybrid), EPHB2 (Affinity Capture-MS), EPHB2 (Affinity Capture-MS), MTMR14 (Two-hybrid), EPHB2 (Biochemical Activity), EPHB2 (Affinity Capture-MS), EPHB2 (Affinity Capture-Western), EPHB2 (Affinity Capture-Western), EPHB2 (Affinity Capture-MS), OXT (Negative Genetic), EPHB2 (Negative Genetic), GPX1 (Negative Genetic)

ESM2 similar proteins: G4V4G1, O13146, O42422, O73798, O77469, O88947, P06213, P08069, P12080, P15127, P15208, P24062, P28693, P29317, P29323, P41413, P54755, P54756, P54757, P54758, P54759, P54762, P54763, P54764, P98092, Q02763, Q02858, Q03145, Q06807, Q07496, Q07497, Q07498, Q08E66, Q14982, Q15375, Q1KL86, Q5IS61, Q60751, Q61772, Q62413

Diamond homologs: A0JNB0, A1Y2K1, A2VDU3, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, F4JTP5, H2KZW3, O01700, O08680, O13146, O13148, O22558, O42422, O43283, O43318, O73878, P00523, P00524, P00525, P00526, P05480, P09759, P0C8E4, P12931, P13115, P13116, P13406, P14085, P15054, P15209, P21709, P27446, P28693, P29318, P29319, P29320, P29323

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
ABL1	down-regulates	EPHB2	phosphorylation
EPHB2	down-regulates	SYNJ1	phosphorylation
EPHB2	“down-regulates activity”	RRAS	phosphorylation
BTF3	“up-regulates quantity by expression”	EPHB2	“transcriptional regulation”
EPHB2	“up-regulates activity”	NRCAM	phosphorylation
EPHB2	“down-regulates quantity by destabilization”	ARHGEF15	phosphorylation
EPHB2	“up-regulates activity”	MYO1B	phosphorylation
EPHB2	“up-regulates quantity”	GRIN2B	phosphorylation
EPHB2	up-regulates	RASA1	binding
EPHB2	up-regulates	SRC	binding
EPHB2	“up-regulates activity”	EPHB2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 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
EPH-ephrin mediated repulsion of cells	7	38.4×	1e-07
EPH-Ephrin signaling	7	29.0×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	6	40.5×	4e-06
axon guidance	7	12.4×	3e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	92
Likely benign	43
Benign	16

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
633783	NM_017449.5(EPHB2):c.2233C>T (p.Arg745Cys)	Pathogenic
8532	NM_017449.5(EPHB2):c.2164C>T (p.Gln722Ter)	Pathogenic

SpliceAI

3427 predictions. Top by Δscore:

Variant	Effect	Δscore
1:22711041:AAGGT:A	donor_loss	1.0000
1:22711042:AGGTG:A	donor_loss	1.0000
1:22711043:GGTG:G	donor_loss	1.0000
1:22784390:A:AG	acceptor_gain	1.0000
1:22784391:G:GG	acceptor_gain	1.0000
1:22863033:TCA:T	acceptor_loss	1.0000
1:22863034:CAG:C	acceptor_loss	1.0000
1:22863035:A:AC	acceptor_loss	1.0000
1:22863035:A:AG	acceptor_gain	1.0000
1:22863036:G:C	acceptor_loss	1.0000
1:22863036:G:GG	acceptor_gain	1.0000
1:22863036:GGT:G	acceptor_gain	1.0000
1:22863036:GGTT:G	acceptor_gain	1.0000
1:22863188:CACAA:C	donor_gain	1.0000
1:22863189:ACAA:A	donor_gain	1.0000
1:22863190:CAA:C	donor_gain	1.0000
1:22863190:CAAG:C	donor_loss	1.0000
1:22863191:AA:A	donor_gain	1.0000
1:22863192:AG:A	donor_loss	1.0000
1:22863193:G:GG	donor_gain	1.0000
1:22863194:TAAG:T	donor_loss	1.0000
1:22864876:GCC:G	acceptor_gain	1.0000
1:22865208:GGCAG:G	donor_gain	1.0000
1:22865209:GCAG:G	donor_gain	1.0000
1:22865209:GCAGG:G	donor_gain	1.0000
1:22865213:G:GG	donor_gain	1.0000
1:22865213:GTAA:G	donor_loss	1.0000
1:22865214:T:G	donor_loss	1.0000
1:22882357:A:AG	acceptor_gain	1.0000
1:22882358:G:GA	acceptor_gain	1.0000

AlphaMissense

6530 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:22781462:T:A	W35R	1.000
1:22781462:T:C	W35R	1.000
1:22781464:G:C	W35C	1.000
1:22781464:G:T	W35C	1.000
1:22784392:T:A	W43R	1.000
1:22784392:T:C	W43R	1.000
1:22784394:G:C	W43C	1.000
1:22784394:G:T	W43C	1.000
1:22784449:T:A	C62S	1.000
1:22784449:T:C	C62R	1.000
1:22784450:G:A	C62Y	1.000
1:22784450:G:C	C62S	1.000
1:22784450:G:T	C62F	1.000
1:22784451:C:G	C62W	1.000
1:22784479:T:A	W72R	1.000
1:22784479:T:C	W72R	1.000
1:22784481:G:C	W72C	1.000
1:22784481:G:T	W72C	1.000
1:22784539:T:C	F92L	1.000
1:22784540:T:C	F92S	1.000
1:22784540:T:G	F92C	1.000
1:22784541:T:A	F92L	1.000
1:22784541:T:G	F92L	1.000
1:22784549:G:C	R95P	1.000
1:22784554:T:A	C97S	1.000
1:22784554:T:C	C97R	1.000
1:22784555:G:A	C97Y	1.000
1:22784555:G:C	C97S	1.000
1:22784556:C:G	C97W	1.000
1:22784584:T:A	C107S	1.000

dbSNP variants (sampled 300 via entrez): RS1000003743 (1:22809884 T>C), RS1000009600 (1:22853711 G>A), RS1000017321 (1:22867459 G>A), RS1000051030 (1:22770528 T>C), RS1000057962 (1:22901348 C>T), RS1000066788 (1:22807193 A>C,T), RS1000072444 (1:22856943 AC>A), RS1000082747 (1:22861430 G>A,C), RS1000089711 (1:22841092 A>G), RS1000145531 (1:22763048 A>G), RS1000153467 (1:22885692 T>C), RS1000154360 (1:22776429 G>C), RS1000178851 (1:22856514 G>A,T), RS1000183480 (1:22914886 G>A,T), RS1000192309 (1:22746423 A>C,G)

Disease associations

OMIM: gene MIM:600997 | disease phenotypes: MIM:604229, MIM:618462, MIM:603688

GenCC curated gene-disease

Disease	Classification	Inheritance
bleeding disorder, platelet-type, 22	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
bleeding disorder, platelet-type, 22	Limited	AR

Mondo (3): Peters anomaly (MONDO:0011414), bleeding disorder, platelet-type, 22 (MONDO:0032765), prostate cancer/brain cancer susceptibility (MONDO:0011361)

Orphanet (2): Peters anomaly (Orphanet:708), Familial prostate cancer (Orphanet:1331)

HPO phenotypes

13 total (14 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001873	Thrombocytopenia
HP:0001933	Subcutaneous hemorrhage
HP:0002239	Gastrointestinal hemorrhage
HP:0004866	Impaired ADP-induced platelet aggregation
HP:0008320	Impaired collagen-induced platelet aggregation
HP:0011463	Childhood onset
HP:0011870	Impaired arachidonic acid-induced platelet aggregation
HP:0011871	Impaired ristocetin-induced platelet aggregation
HP:0011889	Bleeding with minor or no trauma
HP:0012125	Prostate cancer
HP:0030138	Excessive bleeding from superficial cuts
HP:0100006	Neoplasm of the central nervous system
HP:0000659	Peters anomaly

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST006585_2451	Blood protein levels	3.000000e-08
GCST006585_877	Blood protein levels	1.000000e-26
GCST006585_902	Blood protein levels	9.000000e-25
GCST007680_1	Triiodothyronine levels and thyroxine levels	1.000000e-08
GCST007683_1	Triiodothyronine levels	9.000000e-09
GCST010002_354	Refractive error	5.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008392	triiodothyronine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537884	Peters anomaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363043 (PROTEIN FAMILY), CHEMBL3290 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

30 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 280,902 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL5416410	DASATINIB	4	655
CHEMBL217092	SARACATINIB	3	3,982
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL3544983	TESEVATINIB	3	2,819
CHEMBL3545154	POZIOTINIB	3	1,560
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL206834	BAFETINIB	2	1,024
CHEMBL2408045	SAPITINIB	2	1,460
CHEMBL3039525	GOLVATINIB	2
CHEMBL402548	DANUSERTIB	2
CHEMBL403989	TG100-801	2
CHEMBL475251	R-406	2
CHEMBL564829	MILCICLIB	2
CHEMBL572878	TOZASERTIB	2
CHEMBL3544932	TAK-901	1
CHEMBL3545085	XL-228	1
CHEMBL482967	CYC-116	1
CHEMBL574738	AST-487	1

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type XIII RTKs: Ephrin receptor family

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
compound 66 [PMID: 19788238]	Inhibition	8.92	pIC50
RIPK3 inhibitor 18	Inhibition	8.0	pIC50
DDR1/2 inhibitor 5n	Inhibition	6.59	pKd
compound 20 [PMID: 23489211]	Inhibition	5.42	pIC50

Binding affinities (BindingDB)

11 measured of 12 human assays (12 total across all organisms); most potent 11 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
Staurosporine	KD	1.7 nM
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	IC50	10 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
N-[3-[2-[4-amino-1-(1-methylpiperidin-4-yl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	18 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
BMS-354825	KD	27 nM
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide	IC50	33 nM
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide	KD	370 nM
4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	KD	1000 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
CI-1033	KD	1700 nM

ChEMBL bioactivities

122 potent at pChembl≥5 of 141 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.41	Kd	0.39	nM	DASATINIB
8.92	IC50	1.2	nM	CHEMBL566515
8.85	IC50	1.4	nM	CHEMBL6147825
8.70	Kd	2	nM	CHEMBL400402
8.60	IC50	2.5	nM	CHEMBL3752910
8.57	IC50	2.7	nM	DASATINIB ANHYDROUS
8.54	IC50	2.9	nM	CHEMBL4568087
8.41	Kd	3.9	nM	DASATINIB ANHYDROUS
8.41	Kd	3.9	nM	FORETINIB
8.40	Kd	4	nM	DASATINIB
8.40	Kd	3.945	nM	DASATINIB ANHYDROUS
8.36	IC50	4.4	nM	DASATINIB
8.15	Kd	7	nM	CHEMBL249097
8.08	Kd	8.4	nM	BOSUTINIB
8.07	IC50	8.5	nM	BOSUTINIB
8.00	IC50	10	nM	CHEMBL4787515
7.92	Kd	12	nM	CHEMBL4276804
7.76	IC50	17.5	nM	TIVOZANIB
7.72	Kd	19	nM	CHEMBL386051
7.62	IC50	24	nM	TIVOZANIB
7.58	IC50	26	nM	CHEMBL3426225
7.57	IC50	26.8	nM	CHEMBL3426917
7.57	IC50	27.2	nM	CHEMBL5598020
7.48	IC50	33	nM	CHEMBL4798527
7.44	IC50	36	nM	CHEMBL4550702
7.40	EC50	40	nM	CHEMBL559058
7.40	EC50	40	nM	CHEMBL552425
7.37	IC50	42.4	nM	STAUROSPORINE
7.30	IC50	50	nM	CHEMBL445162
7.20	Kd	63	nM	DANUSERTIB
7.18	IC50	65.7	nM	STAUROSPORINE
7.15	IC50	70.8	nM	CHEMBL4638981
7.12	IC50	75	nM	CHEMBL5705847
7.09	IC50	82	nM	CHEMBL1271376
7.03	IC50	93.2	nM	CHEMBL4640297
7.00	EC50	100	nM	CHEMBL552425
6.96	IC50	110	nM	CHEMBL6169335
6.94	IC50	116	nM	STAUROSPORINE
6.89	Kd	130	nM	AST-487
6.83	Kd	149	nM	CHEMBL3688339
6.80	IC50	160	nM	DORAMAPIMOD
6.70	IC50	198.8	nM	STAUROSPORINE
6.64	IC50	230	nM	CHEMBL6173824
6.59	Kd	259	nM	BOSUTINIB
6.58	Kd	260	nM	CHEMBL4168305
6.52	Kd	302	nM	GOLVATINIB
6.51	IC50	310	nM	REBASTINIB
6.36	Kd	440	nM	DORAMAPIMOD
6.36	Kd	440	nM	VANDETANIB
6.35	Kd	448	nM	TIVOZANIB

PubChem BioAssay actives

108 with measured affinity, of 1115 total; 50 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
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	435288: Binding constant for EPHB2 kinase domain	kd	0.0004	uM
7-(5-hydroxy-2-methylphenyl)-6-(2-methoxyphenyl)-4-methylpurino[7,8-a]imidazole-1,3-dione	441393: Inhibition of EphB2 by [gamma33-P]ATP based assay	ic50	0.0012	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0020	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147747: Inhibition of Nano Luc-fused full length C-terminal EPHB2 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0025	uM
Dasatinib	2147747: Inhibition of Nano Luc-fused full length C-terminal EPHB2 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.0027	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637075: Inhibition of recombinant human GST-tagged cytoplasmic EPHB2 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.0029	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625105: Binding constant for EPHB2 kinase domain	kd	0.0039	uM
3-[[4-(5-hydroxy-2-methylanilino)pyrimidin-2-yl]amino]benzamide	389075: Binding affinity to human EPHB2	kd	0.0070	uM
Bosutinib	625105: Binding constant for EPHB2 kinase domain	kd	0.0084	uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637075: Inhibition of recombinant human GST-tagged cytoplasmic EPHB2 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.0100	uM
(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3aS,7aS)-1-[(2S)-2-[[(2S)-2-[[(2S)-3-(acetamidomethylsulfanyl)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]-3-cyclohexylpropanoyl]amino]-3-cyclohexylpropanoyl]amino]propanoyl]amino]-3,3-dimethylbutanoyl]amino]-3-cyclohexylpropanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-cyclohexylpropanoyl]amino]-3-(acetamidomethylsulfanyl)propanoyl]amino]-6-aminohexanoic acid	1424427: Binding affinity to EphB2 (unknown origin) by SPR assay	kd	0.0120	uM
Tivozanib	1206831: Inhibition of recombinant EphB2 (unknown origin) by cell-free assay	ic50	0.0175	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	625105: Binding constant for EPHB2 kinase domain	kd	0.0190	uM
3-[2-(4-amino-1-ethylpyrazolo[3,4-d]pyrimidin-3-yl)ethynyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide	1206229: Inhibition of human EphB2	ic50	0.0260	uM
1-[4-[6,7-bis(trideuteriomethoxy)quinolin-4-yl]oxy-2-chlorophenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea	1206831: Inhibition of recombinant EphB2 (unknown origin) by cell-free assay	ic50	0.0268	uM
2-amino-5-[2-[(3R)-3-aminopyrrolidin-1-yl]-6-fluoro-4-pyridinyl]-3-(3-hydroxy-2,6-dimethylphenyl)benzamide	2122456: Inhibition of EphB2 (unknown origin)	ic50	0.0272	uM
4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637075: Inhibition of recombinant human GST-tagged cytoplasmic EPHB2 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.0360	uM
5-[2-methyl-5-[[3-(trifluoromethyl)phenyl]carbamoyl]anilino]pyridine-3-carboxamide	432943: Inhibition of EphB2	ec50	0.0400	uM
N-[2-methyl-5-[[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]carbamoyl]phenyl]-1,2-oxazole-5-carboxamide	432943: Inhibition of EphB2	ec50	0.0400	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715361: Inhibition of human EPHB2 using poly[Glu:Tyr] (4:1) as substrate by [gamma-33P]-ATP assay	ic50	0.0424	uM
4-N-(5-chloro-1,3-benzodioxol-4-yl)-2-N-(3-methylsulfonylphenyl)pyrimidine-2,4-diamine	331918: Inhibition of EphB2	ic50	0.0500	uM
N-[5-[(2R)-2-methoxy-2-phenylacetyl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0630	uM
N-[3-chloro-4-(4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-5-ylmethyl)phenyl]-3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide	1648815: Inhibition of EPHB2 (unknown origin) assessed as residual activity incubated for 5 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	0.0708	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[(E)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)ethenyl]-4-methylbenzamide	2180125: Inhibition of EphB2 (unknown origin) ACT labeling site by KiNativ Profiling analysis	ic50	0.0750	uM
2-[3-[3-tert-butyl-5-[(2,3-dichlorophenyl)carbamoylamino]pyrazol-1-yl]phenyl]acetamide	525721: Inhibition of EPHB2	ic50	0.0820	uM
N-[4-(1,3a,4,5,7,7a-hexahydropyrazolo[3,4-c]pyridin-6-ylmethyl)-3-chlorophenyl]-3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide	1648815: Inhibition of EPHB2 (unknown origin) assessed as residual activity incubated for 5 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	0.0932	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435288: Binding constant for EPHB2 kinase domain	kd	0.1300	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1490	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	636427: Inhibition of EPHB2	ic50	0.1600	uM
3-(2-imidazo[1,2-a]pyrazin-3-ylethynyl)-N-[3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl]-4-propan-2-ylbenzamide	1356734: Binding affinity to human EPHB2	kd	0.2600	uM
1-N’-[2-fluoro-4-[[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]-4-pyridinyl]oxy]phenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.3020	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168233: Inhibition of human wild type EPHB2 using PolyEY as substrate preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.3100	uM
Vandetanib	435288: Binding constant for EPHB2 kinase domain	kd	0.4400	uM
7-[[(3aS,6aR)-2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]methoxy]-N-(3,4-dichloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.4480	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	625105: Binding constant for EPHB2 kinase domain	kd	0.5600	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147747: Inhibition of Nano Luc-fused full length C-terminal EPHB2 (unknown origin) expressed in HEK293T cells using NanoGlo as substrate incubated for 2 hrs in presence of tracer by NanoBRET assay	ic50	0.6295	uM
Nilotinib	625105: Binding constant for EPHB2 kinase domain	kd	0.6400	uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.6690	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide	2180125: Inhibition of EphB2 (unknown origin) ACT labeling site by KiNativ Profiling analysis	ic50	0.6720	uM
N,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,5-h]quinazoline-3-carboxamide	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.7670	uM
1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[3-[6-(1-methylpyrazol-4-yl)pyrazin-2-yl]oxyphenyl]urea	1236398: Inhibition of EphB2 (unknown origin) using ATP and 5FAM tagged TrkA peptide substrate incubated for 60 mins by microfluidics assay	ic50	0.8800	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	625105: Binding constant for EPHB2 kinase domain	kd	0.8800	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526136: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged EPHB2 (unknown origin) (581 to 986 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.9850	uM
1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-(6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-ylamino)phenyl]urea	1735626: Inhibition of recombinant human EphB2 (560 to end residues) using poly(Glu, Tyr) 4:1 as substrate incubated for 40 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	1.0900	uM
3-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol	240825: Inhibition of EPH receptor B2 using ELISA	ic50	1.2000	uM
5-bromo-4-N-(5-dimethylphosphoryl-2,3-dihydro-1,4-benzodioxin-6-yl)-2-N-[2-methoxy-4-[4-[3-(methoxymethyl)azetidin-1-yl]piperidin-1-yl]-5-methylphenyl]pyrimidine-2,4-diamine	1862875: Inhibition of EphB2 (unknown origin)	ic50	1.2290	uM
[4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenyl] benzoate	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.2960	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	625105: Binding constant for EPHB2 kinase domain	kd	1.4000	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625105: Binding constant for EPHB2 kinase domain	kd	1.5000	uM
Ponatinib	1424992: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.8570	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects methylation, decreases expression, increases expression	5
trichostatin A	decreases expression, affects expression, affects cotreatment	4
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	4
cobaltous chloride	decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
belinostat	affects cotreatment, decreases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
Cisplatin	affects cotreatment, decreases expression	2
Lipopolysaccharides	decreases expression, increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
NVP-BHG712	affects reaction, increases expression, decreases reaction	1
lly-283	decreases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
titanium dioxide	decreases phosphorylation	1
beta-lapachone	decreases expression	1
arsenite	decreases methylation	1
sodium bichromate	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
butyraldehyde	increases expression	1
saikosaponin D	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	affects methylation, increases methylation	1
cupric chloride	increases expression	1

ChEMBL screening assays

312 unique, capped per target: 311 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1024913	Binding	Binding affinity to human EPHB2 at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — J Med Chem
CHEMBL875576	Functional	Inhibition of ephrin-B1-mediated EPH receptor B2 autophosphorylation	Frontal affinity chromatography with MS detection of EphB2 tyrosine kinase receptor. 2. Identification of small-molecule inhibitors via coupling with virtual screening. — J Med Chem

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8FE	Abcam HCT 116 EPHB2 KO	Cancer cell line	Male
CVCL_B8VA	Abcam MCF-7 EPHB2 KO	Cancer cell line	Female
CVCL_B9HM	Abcam A-549 EPHB2 KO	Cancer cell line	Male
CVCL_SM19	HAP1 EPHB2 (-) 1	Cancer cell line	Male
CVCL_SM20	HAP1 EPHB2 (-) 2	Cancer cell line	Male
CVCL_SM21	HAP1 EPHB2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford