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MGP000963

UniProt Annotations

Entry Information
Gene NameEPH receptor A4
Protein Entry
UniProt ID
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; IsoId=P54764-1; Sequence=Displayed; Name=2; IsoId=P54764-2; Sequence=VSP_056016; Note=No experimental confirmation available.;
Catalytic ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE- ProRule:PRU10028}.
DomainThe protein kinase domain mediates interaction with NGEF. {ECO:0000250}.
FunctionReceptor 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. {ECO:0000269|PubMed:17143272}.
SimilarityBelongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily. {ECO:0000255|PROSITE- ProRule:PRU00159}.
SimilarityContains 1 Eph LBD (Eph ligand-binding) domain. {ECO:0000255|PROSITE-ProRule:PRU00883}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 SAM (sterile alpha motif) domain. {ECO:0000255|PROSITE-ProRule:PRU00184}.
SimilarityContains 2 fibronectin type-III domains. {ECO:0000255|PROSITE-ProRule:PRU00316}.
Subcellular LocationCell membrane {ECO:0000250}; Single-pass type I membrane protein {ECO:0000250}. Cell projection, axon {ECO:0000250}. Cell projection, dendrite {ECO:0000250}. Cell junction, synapse, postsynaptic cell membrane, postsynaptic density {ECO:0000250}. Early endosome {ECO:0000250}. Note=Clustered upon activation and targeted to early endosome. {ECO:0000250}.
SubunitHeterotetramer 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. {ECO:0000250, ECO:0000269|PubMed:18094260, ECO:0000269|PubMed:19836338, ECO:0000269|PubMed:19875447}.
Tissue SpecificityUbiquitous.
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