UniProt functional annotation for Q03137



	UniProt functional annotation for Q03137

UniProt code: Q03137.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

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, 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. 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 (PubMed:30639848). {ECO:0000269|PubMed:15537875, ECO:0000269|PubMed:16802330, ECO:0000269|PubMed:16818734, ECO:0000269|PubMed:17143272, ECO:0000269|PubMed:17719550, ECO:0000269|PubMed:17785183, ECO:0000269|PubMed:18094260, ECO:0000269|PubMed:18403711, ECO:0000269|PubMed:30639848, ECO:0000269|PubMed:9789074}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};

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 (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. 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. Forms a ternary complex composed of ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by ADAM10 which disrupts adherens junctions (PubMed:30639848). {ECO:0000269|PubMed:11336673, ECO:0000269|PubMed:17143272, ECO:0000269|PubMed:17719550, ECO:0000269|PubMed:17785183, ECO:0000269|PubMed:18094260, ECO:0000269|PubMed:30639848, ECO:0000269|PubMed:8622893}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:17143272}; Single-pass type I membrane protein {ECO:0000269|PubMed:17143272}. Cell projection, axon {ECO:0000269|PubMed:17143272}. Cell projection, dendrite {ECO:0000269|PubMed:17143272}. Cell junction, synapse, postsynaptic density membrane {ECO:0000250}. Early endosome {ECO:0000269|PubMed:17143272}. Cell junction, adherens junction {ECO:0000269|PubMed:30639848}. Note=Clustered upon activation and targeted to early endosome.

Tissue specificity: Expressed in inner and outer pillar cells of the organ of Corti (at protein level) (PubMed:30639848). Highest expression in the adult brain and retina and also detectable in kidney, lung, skeletal muscle and thymus. Not detected in heart and liver. Expressed in myogenic progenitor cells (PubMed:27446912). {ECO:0000269|PubMed:27446912, ECO:0000269|PubMed:30639848}.

Developmental stage: Found in both the 10-day embryonic brain and body tissues. In the embryonic brain, expressed in the developing cortex of the telencephalon and major cortical tracts. Also expressed in the hippocampus, fornix and striatal cells and tracts. In the diencephalon, strongly expressed in thalamus, hypothalamus and thalamo-cortical projection. Also expressed in red nuclei of the mesencephalon and in the cerebellum. In the spinal cord, persistent expression occurs in the dorsal funiculus and ventral gray matter. In myogenic progenitor cells, highly expressed at 11.5 dpc and ceases its expression at the late fetal stage (17.5 dpc) (PubMed:27446912). {ECO:0000269|PubMed:14516691, ECO:0000269|PubMed:27446912}.

Domain: The protein kinase domain mediates interaction with NGEF.

Disruption phenotype: Mice are viable and fertile but display a loss of coordination of limb movement associated with disruptions of cortico- spinal tract. They also display altered development of the thymic epithelium which leads to a defective T-cells development. {ECO:0000269|PubMed:15537875, ECO:0000269|PubMed:16818734, ECO:0000269|PubMed:9789074}.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily. {ECO:0000255|PROSITE- ProRule:PRU00159}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



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, 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. 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 (PubMed:30639848). {ECO:0000269\|PubMed:15537875, ECO:0000269\|PubMed:16802330, ECO:0000269\|PubMed:16818734, ECO:0000269\|PubMed:17143272, ECO:0000269\|PubMed:17719550, ECO:0000269\|PubMed:17785183, ECO:0000269\|PubMed:18094260, ECO:0000269\|PubMed:18403711, ECO:0000269\|PubMed:30639848, ECO:0000269\|PubMed:9789074}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028};
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 (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. 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. Forms a ternary complex composed of ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by ADAM10 which disrupts adherens junctions (PubMed:30639848). {ECO:0000269\|PubMed:11336673, ECO:0000269\|PubMed:17143272, ECO:0000269\|PubMed:17719550, ECO:0000269\|PubMed:17785183, ECO:0000269\|PubMed:18094260, ECO:0000269\|PubMed:30639848, ECO:0000269\|PubMed:8622893}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:17143272}; Single-pass type I membrane protein {ECO:0000269\|PubMed:17143272}. Cell projection, axon {ECO:0000269\|PubMed:17143272}. Cell projection, dendrite {ECO:0000269\|PubMed:17143272}. Cell junction, synapse, postsynaptic density membrane {ECO:0000250}. Early endosome {ECO:0000269\|PubMed:17143272}. Cell junction, adherens junction {ECO:0000269\|PubMed:30639848}. Note=Clustered upon activation and targeted to early endosome.
Tissue specificity:		Expressed in inner and outer pillar cells of the organ of Corti (at protein level) (PubMed:30639848). Highest expression in the adult brain and retina and also detectable in kidney, lung, skeletal muscle and thymus. Not detected in heart and liver. Expressed in myogenic progenitor cells (PubMed:27446912). {ECO:0000269\|PubMed:27446912, ECO:0000269\|PubMed:30639848}.
Developmental stage:		Found in both the 10-day embryonic brain and body tissues. In the embryonic brain, expressed in the developing cortex of the telencephalon and major cortical tracts. Also expressed in the hippocampus, fornix and striatal cells and tracts. In the diencephalon, strongly expressed in thalamus, hypothalamus and thalamo-cortical projection. Also expressed in red nuclei of the mesencephalon and in the cerebellum. In the spinal cord, persistent expression occurs in the dorsal funiculus and ventral gray matter. In myogenic progenitor cells, highly expressed at 11.5 dpc and ceases its expression at the late fetal stage (17.5 dpc) (PubMed:27446912). {ECO:0000269\|PubMed:14516691, ECO:0000269\|PubMed:27446912}.
Domain:		The protein kinase domain mediates interaction with NGEF.
Disruption phenotype:		Mice are viable and fertile but display a loss of coordination of limb movement associated with disruptions of cortico- spinal tract. They also display altered development of the thymic epithelium which leads to a defective T-cells development. {ECO:0000269\|PubMed:15537875, ECO:0000269\|PubMed:16818734, ECO:0000269\|PubMed:9789074}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00159}.