Tchem EPHA4 Ephrin type-A receptor 4

Protein Classes

DTO Classes

Protein / Kinase / Protein Kinase / Tk Group / Eph Family / Ephrin Type-a Receptor 4

Protein Summary

Description

Receptor tyrosine kinase which binds membrane-bound ephrin 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. Highly promiscuous, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. In addition to its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, plays also a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium. This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

Uniprot Accession IDs

• P54764
• A8K2P1
• B2R601
• B7Z6Q8
• Q2M380

Gene Name

• EPHA4

Ensembl ID

• ENST00000281821
• ENSP00000281821
• ENSG00000116106
• ENST00000409938
• ENSP00000386829

Symbol

• HEK8
• SEK
• TYRO1
• EK8
• SEK
• HEK8
• TYRO1

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
molecular function	1
protein domain	1
biological process	0.97
PubMedID	0.97
transcription factor perturbation	0.96

Related Tools

ProKinO

The ProKinO is a protein kinase-specific ontology, which provides a controlled vocabulary of terms, their hierarchy, and relationships unifying sequence, structure, function, mutation and pathway information on kinases.

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Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

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GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

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GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 351.34   (req: < 5)

Gene RIFs: 41   (req: <= 3)

Antibodies: 635   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 351.34   (req: >= 5)

Gene RIFs: 41   (req: > 3)

Antibodies: 635   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 48

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 6

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drugs: 2

Approved Drugs (2)

Explore Approved Drugs

1 – 2 of 2

bosutinib

EPHA4Tchem Kinase

Kd : 7.74

dasatinib

EPHA4Tchem Kinase

Kd : 8.92

Active Ligands (6)

Explore Active Ligands

1 – 6 of 6

CHEMBL1230609

EPHA4Tchem Kinase

Kd : 8.72

CHEMBL386051

EPHA4Tchem Kinase

Kd : 8.08

CHEMBL249097

EPHA4Tchem Kinase

Kd : 8.3

CHEMBL566515

EPHA4Tchem Kinase

IC50 : 8.48

compound 20 [PMID: 23489211]

EPHA4Tchem Kinase

IC50 : 5.57000017

CHEMBL3787112

EPHA4Tchem Kinase

IC50 : 8.05

GWAS Traits (1)

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GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
heel bone mineral density	EFO_0009270	2	1	2		80.6

• Explore on Target Illumination GWAS Analytics (TIGA)

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
heel bone mineral density	EFO_0009270	2		80.6

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Orthologs (13)

1 – 5 of 13

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	EPH receptor A4	VGNC:10781	470660
Macaque	EPH receptor A4		704857
Mouse	Eph receptor A4	MGI:98277	13838
Rat	Eph receptor A4	RGD:1560587	316539
Dog	EPH receptor A4	VGNC:40407	478925

Species	Name	OMA	EggNOG	Inparanoid
Chimp	EPH receptor A4
Macaque	EPH receptor A4
Mouse	Eph receptor A4
Rat	Eph receptor A4
Dog	EPH receptor A4

Protein Structure (15 Structures, 1 AlphaFold Model)

Representation

  axes   backbone   ball+stick   cartoon   rocket   rope   spacefill

Color Scheme

  target   atomindex   bfactor   chainname   electrostatic   element   hydrophobicity   resname   sstruc

Click on a row in the table to change the structure displayed.
More information can be found at RCSB PDB

AF-P54764-F1-model_v1

AlphaFold Structures Developed by DeepMind and EMBL-EBI

1 – 5 of 15

PDB Structure Id	Ligand	Method	Resolution (Å)	Residues	Fraction of Total Protein	Pub Year	Title

PDB Structure Id	Fraction of Total Protein	Resolution	Pub Year

Pathways (11)

Reactome (4)

KEGG (1)

PathwayCommons (3)

WikiPathways (3)

Axon guidance (R-HSA-422475)

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Find Similar Targets

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Axon guidance	533 targets	R-HSA-422475
Reactome	Developmental Biology	1055 targets	R-HSA-1266738
Reactome	EPH-Ephrin signaling	92 targets	R-HSA-2682334
Reactome	EPH-ephrin mediated repulsion of cells	49 targets	R-HSA-3928665

Name	Explore in Pharos	Explore in Source
Axon guidance	533 targets	R-HSA-422475
Developmental Biology	1055 targets	R-HSA-1266738
EPH-Ephrin signaling	92 targets	R-HSA-2682334
EPH-ephrin mediated repulsion of cells	49 targets	R-HSA-3928665

Gene Ontology Terms (73)

Functions (13)

Components (25)

Processes (35)

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Items per page:

10

1 – 10 of 13

GO Term	Evidence	Assigned by
DH domain binding	Inferred from Direct Assay (IDA)	UniProtKB
protein kinase activity	Inferred from Direct Assay (IDA)	UniProtKB
PH domain binding	Inferred from Physical Interaction (IPI)	UniProtKB
protein tyrosine kinase binding	Inferred from Physical Interaction (IPI)	ARUK-UCL
kinase activity	Inferred from Genetic Interaction (IGI)	ARUK-UCL
transmembrane receptor protein tyrosine kinase activity	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
transmembrane signaling receptor activity	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
GPI-linked ephrin receptor activity	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
transmembrane-ephrin receptor activity	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
amyloid-beta binding	Traceable Author Statement (TAS)	ARUK-UCL

Protein-Protein Interactions (184)

Explore Interacting Targets

1 – 10 of 184

• See Interactions on String-DB

EFNA5

Tbio

Novelty: 0.00134985

p_int: 0.999418723

p_ni: 0.000581277

Score: 0.999

Data Source: BioPlex,STRINGDB

IARS2

Tbio

Family: Enzyme

Novelty: 0.00854621

p_int: 0.99924068

p_ni: 0.00075932

Data Source: BioPlex

CALML3

Tbio

Novelty: 0.0336689

p_int: 0.99884891

p_ni: 0.001151028

p_wrong: 6.3e-8

Data Source: BioPlex

COPZ1

Tbio

Novelty: 0.01405958

p_int: 0.998231872

p_ni: 0.001768128

p_wrong: 1e-9

Data Source: BioPlex

RSPH14

Tdark

Novelty: 0.53463266

p_int: 0.99772695

p_ni: 0.00227305

Score: 0.199

Data Source: BioPlex,STRINGDB

CPA5

Tbio

Family: Enzyme

Novelty: 0.0516555

p_int: 0.992916647

p_ni: 0.007083353

Data Source: BioPlex

TBC1D22A

Tbio

Novelty: 0.46374046

p_int: 0.992244291

p_ni: 0.007755709

Score: 0.154

Data Source: BioPlex,STRINGDB

CTLA4

Tclin

Novelty: 0.00012781

p_int: 0.987411446

p_ni: 0.012588513

p_wrong: 4e-8

Data Source: BioPlex

TUBB

Tclin

Novelty: 0.0038007

p_int: 0.98695319

p_ni: 0.01304681

Score: 0.158

Data Source: BioPlex,STRINGDB

TMEM9

Tbio

Novelty: 0.06916197

p_int: 0.98106841

p_ni: 0.01893159

Data Source: BioPlex

Publication Statistics

PubMed Score  351.34

PubMed score by year

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PubTator Score  116.72

PubTator score by year

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Patents

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Amino Acid Sequence

Residue Counts

Protein Sequence

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Ortholog Sequence Conservation

WebLogo Color Code

PolarG S T Y C

NeutralQ N

BasicK R H

AcidicD E

HydrophobicA V L I P W F M

Compare across kinases on ProKinO

Structural Annotations

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UniProt Keyword Find Similar Targets

3D-structure
Alternative splicing
ATP-binding
Cell adhesion
Cell junction
Cell membrane
Cell projection
Complete proteome
Developmental protein
Endosome

GWAS Trait Find Similar Targets

heel bone mineral density

MGI Phenotype Find Similar Targets

behavior/neurological phenotype
cellular phenotype
endocrine/exocrine gland phenotype
nervous system phenotype
reproductive system phenotype