Reactome | UniProt:P54764 EPHA4

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UniProt:P54764 EPHA4 Show undefined attributes

chain	signal peptide:1-19 chain:20-986
checksum	0C39C1152EDDD46F
comment	FUNCTION 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, also plays 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. During development of the cochlear organ of Corti, regulates pillar cell separation by forming a ternary complex with ADAM10 and CADH1 which facilitates the cleavage of CADH1 by ADAM10 and disruption of adherens junctions (By similarity). Phosphorylates CAPRIN1, promoting CAPRIN1-dependent formation of a membraneless compartment (By similarity).CATALYTIC ACTIVITY L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+)SUBUNIT Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. Interacts (phosphorylated at position Tyr-602) with FYN. Interacts with CDK5, CDK5R1 and NGEF; upon activation by EFNA1 induces NGEF phosphorylation by the kinase CDK5. Interacts with CHN1; effector of EPHA4 in axon guidance linking EPHA4 activation to RAC1 regulation (By similarity). Interacts (via PDZ motif) with SIPA1L1 (via PDZ domain); controls neuronal morphology through regulation of the RAP1 (RAP1A or RAP1B) and RAP2 (RAP2A, RAP2B or RAP2C) GTPases. Forms a ternary complex composed of ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by ADAM10 which disrupts adherens junctions (By similarity).INTERACTION Clustered upon activation and targeted to early endosome.ALTERNATIVE PRODUCTS Ubiquitous.DOMAIN The protein kinase domain mediates interaction with NGEF.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.
crossReference	[DatabaseIdentifier:11506879] ENSEMBL:ENSG00000116106 [DatabaseIdentifier:12818251] ZINC - World Drugs:EPHA4_HUMAN [DatabaseIdentifier:12815464] ZINC target:P54764 [DatabaseIdentifier:12812112] ZINC - Substances:EPHA4_HUMAN [DatabaseIdentifier:12810194] ZINC - Predictions - Purchasable:EPHA4_HUMAN [DatabaseIdentifier:12806745] ZINC - Investigational:EPHA4_HUMAN [DatabaseIdentifier:12805670] ZINC - FDA approved:EPHA4_HUMAN [DatabaseIdentifier:12804534] ZINC - Biogenic:EPHA4_HUMAN [DatabaseIdentifier:12443223] RefSeq:NP_004429.1 [DatabaseIdentifier:12443222] RefSeq:NP_001291465.1 [DatabaseIdentifier:12443221] RefSeq:NP_001291466.1 [DatabaseIdentifier:12281524] Pharos - Targets:P54764 [DatabaseIdentifier:12259489] PRO:P54764 [DatabaseIdentifier:12152813] PDB:4M4P [DatabaseIdentifier:12152811] PDB:2LW8 [DatabaseIdentifier:12152824] PDB:2WO1 [DatabaseIdentifier:12152817] PDB:2WO3 [DatabaseIdentifier:12152820] PDB:7OFV [DatabaseIdentifier:12152819] PDB:4W4Z [DatabaseIdentifier:12152823] PDB:4BKA [DatabaseIdentifier:12152818] PDB:4BKF [DatabaseIdentifier:12152822] PDB:3CKH [DatabaseIdentifier:12152814] PDB:4BK4 [DatabaseIdentifier:12152821] PDB:9CY8 [DatabaseIdentifier:12152809] PDB:4W50 [DatabaseIdentifier:12152816] PDB:2WO2 [DatabaseIdentifier:12152810] PDB:3GXU [DatabaseIdentifier:12152815] PDB:4M4R [DatabaseIdentifier:12152812] PDB:5JR2 [DatabaseIdentifier:12152808] PDB:4BK5 [DatabaseIdentifier:12121195] OpenTargets:ENSG00000116106 [DatabaseIdentifier:11620306] ENSEMBL:ENSP00000386829 [DatabaseIdentifier:11620307] ENSEMBL:ENSP00000281821 [DatabaseIdentifier:11743005] ENSEMBL:ENST00000409938 [DatabaseIdentifier:11743006] ENSEMBL:ENST00000281821 [DatabaseIdentifier:11780612] Guide to Pharmacology - Targets:1824 [DatabaseIdentifier:11783609] GeneCards:EPHA4 [DatabaseIdentifier:11799165] GlyGen:P54764 [DatabaseIdentifier:11831086] HMDB Protein:HMDBP01429 [DatabaseIdentifier:11836715] HPA:ENSG00000116106-EPHA4
databaseName	UniProt
dbId	54368
description	recommendedName: Ephrin type-A receptor 4 ecNumber: 2.7.10.1 alternativeName: EPH-like kinase 8 shortName: EK8 shortName: hEK8 alternativeName: Tyrosine-protein kinase TYRO1 alternativeName: Tyrosine-protein kinase receptor SEK
displayName	UniProt:P54764 EPHA4
geneName	EPHA4 HEK8 SEK TYRO1
identifier	P54764
isSequenceChanged	false
keyword	3D-structure Alternative splicing ATP-binding Cell adhesion Cell junction Cell membrane Cell projection Developmental protein Endosome Glycoprotein Kinase Membrane Neurogenesis Nucleotide-binding Phosphoprotein Postsynaptic cell membrane Proteomics identification Receptor Reference proteome Repeat Signal Synapse Transferase Transmembrane Transmembrane helix Tyrosine-protein kinase
modified	[InstanceEdit:9939033] Weiser, Joel, 2025-02-21
moleculeType	Protein
name	EPHA4
otherIdentifier	11723440_a_at 11723441_a_at 11723442_at 11723443_at 1606_at 16908897 2043 206114_PM_at 206114_at 227449_PM_at 227449_at 228948_PM_at 228948_at 229374_PM_at 229374_at 238671_PM_at 238671_at 2600690 2600691 2600692 2600693 2600694 2600695 2600696 2600697 2600698 2600699 2600700 2600701 2600702 2600703 2600704 2600708 2600709 2600711 2600713 2600721 2600723 2600725 2600728 2600730 2600731 2600743 2600746 2600767 2600769 2600773 2600774 2600776 53937_at 62566_at 63932_at 8059279 92100_at A_23_P108501 A_23_P119899 A_24_P274219 GE79501 GE80223 GO:0000166 GO:0000290 GO:0001540 GO:0003824 GO:0004672 GO:0004713 GO:0004714 GO:0005003 GO:0005004 GO:0005005 GO:0005515 GO:0005524 GO:0005737 GO:0005741 GO:0005768 GO:0005769 GO:0005886 GO:0005912 GO:0006468 GO:0007155 GO:0007162 GO:0007169 GO:0007399 GO:0007411 GO:0007628 GO:0008045 GO:0008284 GO:0008347 GO:0009986 GO:0010719 GO:0010977 GO:0014069 GO:0016020 GO:0016301 GO:0016740 GO:0017148 GO:0021957 GO:0030175 GO:0030335 GO:0030336 GO:0030424 GO:0030425 GO:0031594 GO:0031901 GO:0034330 GO:0034332 GO:0042731 GO:0042734 GO:0042802 GO:0042995 GO:0043087 GO:0043197 GO:0043198 GO:0043204 GO:0043226 GO:0043524 GO:0043679 GO:0044295 GO:0044297 GO:0045202 GO:0045211 GO:0045785 GO:0045947 GO:0046330 GO:0046875 GO:0048013 GO:0048681 GO:0048710 GO:0048856 GO:0048870 GO:0050770 GO:0050775 GO:0050821 GO:0060384 GO:0061001 GO:0070161 GO:0070373 GO:0072178 GO:0090102 GO:0097155 GO:0097156 GO:0097161 GO:0097485 GO:0098685 GO:0098839 GO:0098883 GO:0098978 GO:0106030 GO:0140096 GO:0140694 GO:1900038 GO:1900272 GO:1902004 GO:1902533 GO:1902993 GO:1903051 GO:1904646 GO:1905244 GO:1905806 GO:1990782 HMNXSV003043201 Hs.173596.0.A1_3p_at Hs.244624.0.A1_3p_at Hs.244624.1.A1_3p_at Hs.314784.0.A1_3p_at ILMN_1672022 L36645_at PH_hs_0004230 PH_hs_0013017 TC02002808.hg g4758279_3p_at
physicalEntity	[EntityWithAccessionedSequence:R-HSA-3928352] p-Y596,Y602-EPHA4 [plasma membrane] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-2682325] EPHA4 [plasma membrane] - Homo sapiens
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:11910082] KEGG:hsa:2043 EPHA4 [ReferenceDNASequence:12760580] UCSC:P54764 EPHA4 [ReferenceDNASequence:12106924] OMIM:602188 EPHA4 [ReferenceDNASequence:12085988] NCBI Gene:2043 EPHA4 [ReferenceDNASequence:12001895] Monarch:2043 EPHA4 [ReferenceDNASequence:ensembl:ENSG00000116106] ENSEMBL:ENSG00000116106 EPHA4 [ReferenceDNASequence:11372106] BioGPS Gene:2043 EPHA4 [ReferenceDNASequence:11402706] COSMIC - genes:EPHA4 EPHA4 [ReferenceDNASequence:11407308] CTD Gene:2043 EPHA4 [ReferenceDNASequence:11440222] dbSNP Gene:2043 EPHA4 [ReferenceDNASequence:11815227] HGNC:3388 EPHA4
referenceTranscript	[ReferenceRNASequence:12624778] RefSeq:NM_004438.5 EPHA4 [ReferenceRNASequence:12624779] RefSeq:NM_001304536.2 EPHA4 [ReferenceRNASequence:12624780] RefSeq:NM_001304537.2 EPHA4
schemaClass	ReferenceGeneProduct
secondaryIdentifier	EPHA4_HUMAN A8K2P1 B2R601 B7Z6Q8 Q2M380
sequenceLength	986
species	[Species:48887] Homo sapiens
stId	uniprot:P54764
url	http://purl.uniprot.org/uniprot/P54764

Referrals

(referenceEntity)	[EntityWithAccessionedSequence:R-HSA-3928352] p-Y596,Y602-EPHA4 [plasma membrane] [EntityWithAccessionedSequence:R-HSA-2682325] EPHA4 [plasma membrane]
(referenceSequence)	[ModifiedResidue:3928328] O4'-phospho-L-tyrosine at 602 [ModifiedResidue:3928354] O4'-phospho-L-tyrosine at 596
(interactor)	[UndirectedInteraction:11133249] UniProt:Q9NSE4 <-> UniProt:P54764 (IntAct) [UndirectedInteraction:11170405] UniProt:P29323 <-> UniProt:P54764 (IntAct) [UndirectedInteraction:11171809] UniProt:Q96PP8 <-> UniProt:P54764 (IntAct) [UndirectedInteraction:11188359] UniProt:P54764 <-> UniProt:P52803 (IntAct) [UndirectedInteraction:11188361] UniProt:P54764 <-> UniProt:P52799 (IntAct) [UndirectedInteraction:11188363] UniProt:P54764 <-> UniProt:Q15768 (IntAct) [UndirectedInteraction:11188365] UniProt:P54764 <-> UniProt:P52798 (IntAct) [UndirectedInteraction:11188367] UniProt:P54764 <-> UniProt:O43921 (IntAct) [UndirectedInteraction:11188369] UniProt:P54764 <-> UniProt:Q9BVA1 (IntAct) [UndirectedInteraction:11188371] UniProt:P54764 <-> UniProt:P20827 (IntAct) [UndirectedInteraction:11188373] UniProt:P54764 <-> UniProt:P98172 (IntAct) [UndirectedInteraction:11188375] UniProt:P54764 <-> UniProt:P62158 (IntAct) [UndirectedInteraction:11188377] UniProt:P54764 <-> UniProt:P11172 (IntAct) [UndirectedInteraction:11188379] UniProt:P54764 <-> UniProt:P07148 (IntAct) [UndirectedInteraction:11188381] UniProt:P54764 <-> UniProt:A4D1S0 (IntAct) [UndirectedInteraction:11188383] UniProt:P54764 <-> UniProt:P07437 (IntAct) [UndirectedInteraction:11188385] UniProt:P54764 <-> UniProt:Q8WXQ8 (IntAct) [UndirectedInteraction:11188387] UniProt:P54764 <-> UniProt:P04350 (IntAct) [UndirectedInteraction:11188389] UniProt:P54764 <-> UniProt:Q9UHP6 (IntAct) [UndirectedInteraction:11188391] UniProt:P54764 <-> UniProt:Q13438 (IntAct) [UndirectedInteraction:11188393] UniProt:P54764 <-> UniProt:P19086 (IntAct) [UndirectedInteraction:11188395] UniProt:P54764 <-> UniProt:P35249 (IntAct) [UndirectedInteraction:11188397] UniProt:P54764 <-> UniProt:Q9UHW5 (IntAct) [UndirectedInteraction:11188399] UniProt:P54764 <-> UniProt:P05177 (IntAct) [UndirectedInteraction:11188403] UniProt:P54764 <-> UniProt:Q9NRE1 (IntAct) [UndirectedInteraction:11188405] UniProt:P54764 <-> UniProt:O60637 (IntAct) [UndirectedInteraction:11188407] UniProt:P54764 <-> UniProt:Q9BPY3 (IntAct)