UniProt functional annotation for P29317



	UniProt functional annotation for P29317

UniProt code: P29317.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Receptor tyrosine kinase which binds promiscuously membrane- bound ephrin-A 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. Activated by the ligand ephrin- A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand- independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:16236711, ECO:0000269|PubMed:18339848, ECO:0000269|PubMed:19573808, ECO:0000269|PubMed:20679435, ECO:0000269|PubMed:20861311, ECO:0000269|PubMed:23358419, ECO:0000269|PubMed:26158630, ECO:0000269|PubMed:27385333}.

Function: (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins. {ECO:0000269|PubMed:21516087}.

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, ECO:0000269|PubMed:2174105};

Subunit: Homodimer. Interacts with SLA. Interacts (phosphorylated form) with VAV2, VAV3 and PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3); critical for the EFNA1-induced activation of RAC1 which stimulates cell migration (By similarity). Interacts with INPPL1; regulates activated EPHA2 endocytosis and degradation. Interacts (inactivated form) with PTK2/FAK1 and interacts (EFNA1 ligand-activated form) with PTPN11; regulates integrin-mediated adhesion. Interacts with ARHGEF16, DOCK4 and ELMO2; mediates ligand-independent activation of RAC1 which stimulates cell migration. Interacts with CLDN4; phosphorylates CLDN4 and may regulate tight junctions. Interacts with ACP1. Interacts (via SAM domain) with ANKS1A (via SAM domain). Interacts with CEMIP. Interacts with NCK1; may regulate EPHA2 activity in cell migration and adhesion. {ECO:0000250|UniProtKB:Q03145, ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:12167657, ECO:0000269|PubMed:16236711, ECO:0000269|PubMed:17135240, ECO:0000269|PubMed:19525919, ECO:0000269|PubMed:20505120, ECO:0000269|PubMed:20679435, ECO:0000269|PubMed:22332920, ECO:0000269|PubMed:23358419, ECO:0000269|PubMed:23936024}.

Subunit: (Microbial infection) Interacts with human herpes virus 8/HHV- 8 glycoprotein L/gL and glycoprotein H/gH heterodimer; this interaction triggers EPHA2 phosphorylation and endocytosis, allowing virus entry. {ECO:0000269|PubMed:22635007}.

Subunit: (Microbial infection) Interacts with Epstein-Barr virus/HHV-4 glycoprotein L/gL and glycoprotein H/gH heterodimer; this interaction facilitates virus internalization and fusion. {ECO:0000269|PubMed:29292383, ECO:0000269|PubMed:29292384}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:18794797, ECO:0000269|PubMed:19573808, ECO:0000269|PubMed:20223987, ECO:0000269|PubMed:20861311}; Single-pass type I membrane protein {ECO:0000255}. Cell projection, ruffle membrane {ECO:0000269|PubMed:19573808}; Single-pass type I membrane protein {ECO:0000255}. Cell projection, lamellipodium membrane {ECO:0000269|PubMed:19573808}; Single-pass type I membrane protein {ECO:0000255}. Cell junction, focal adhesion {ECO:0000269|PubMed:10655584}. Note=Present at regions of cell-cell contacts but also at the leading edge of migrating cells (PubMed:19573808, PubMed:20861311). Relocates from the plasma membrane to the cytoplasmic and perinuclear regions in cancer cells (PubMed:18794797). {ECO:0000269|PubMed:18794797, ECO:0000269|PubMed:19573808, ECO:0000269|PubMed:20861311, ECO:0000269|PubMed:26158630}.

Tissue specificity: Expressed in brain and glioma tissue and glioma cell lines (at protein level). Expressed most highly in tissues that contain a high proportion of epithelial cells, e.g. skin, intestine, lung, and ovary. {ECO:0000269|PubMed:17332925}.

Induction: Up-regulated by UV irradiation via a TP53-independent, MAPK- dependent mechanism. {ECO:0000269|PubMed:18339848}.

Ptm: Autophosphorylates. Phosphorylated on tyrosine upon binding and activation by EFNA1. Phosphorylated residues Tyr-588 and Tyr-594 are required for binding VAV2 and VAV3 while phosphorylated residues Tyr- 735 and Tyr-930 are required for binding PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3). These phosphorylated residues are critical for recruitment of VAV2 and VAV3 and PI3-kinase p85 subunit which transduce downstream signaling to activate RAC1 GTPase and cell migration. Dephosphorylation of Tyr-930 by PTPRF prevents the interaction of EPHA2 with NCK1. Phosphorylated at Ser-897 by PKB; serum-induced phosphorylation which targets EPHA2 to the cell leading edge and stimulates cell migration. Phosphorylation by PKB is inhibited by EFNA1-activated EPHA2 which regulates PKB activity via a reciprocal regulatory loop. Phosphorylated at Ser-897 in response to TNF by RPS6KA1 and RPS6KA3; RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). Phosphorylated at Ser-897 by PKA; blocks cell retraction induced by EPHA2 kinase activity (PubMed:27385333). Dephosphorylated by ACP1. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:18794797, ECO:0000269|PubMed:19573808, ECO:0000269|PubMed:23358419, ECO:0000269|PubMed:26158630, ECO:0000269|PubMed:27385333}.

Ptm: Ubiquitinated by CHIP/STUB1. Ubiquitination is regulated by the HSP90 chaperone and regulates the receptor stability and activity through proteasomal degradation. ANKS1A prevents ubiquitination and degradation (By similarity). {ECO:0000250}.

Disease: Cataract 6, multiple types (CTRCT6) [MIM:116600]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT6 includes posterior polar and age-related cortical cataracts, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. Age-related cortical cataract is a developmental punctate opacity restricted to the cortex. The cataract is white or cerulean, increases in number with age, but rarely affects vision. {ECO:0000269|PubMed:19005574, ECO:0000269|PubMed:19306328, ECO:0000269|PubMed:19649315, ECO:0000269|PubMed:22570727}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Note=Overexpressed in several cancer types and promotes malignancy. {ECO:0000269|PubMed:19573808}.

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:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Receptor tyrosine kinase which binds promiscuously membrane- bound ephrin-A 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. Activated by the ligand ephrin- A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand- independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis. {ECO:0000269\|PubMed:10655584, ECO:0000269\|PubMed:16236711, ECO:0000269\|PubMed:18339848, ECO:0000269\|PubMed:19573808, ECO:0000269\|PubMed:20679435, ECO:0000269\|PubMed:20861311, ECO:0000269\|PubMed:23358419, ECO:0000269\|PubMed:26158630, ECO:0000269\|PubMed:27385333}.



Function:		(Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins. {ECO:0000269\|PubMed:21516087}.


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, ECO:0000269\|PubMed:2174105};
Subunit:		Homodimer. Interacts with SLA. Interacts (phosphorylated form) with VAV2, VAV3 and PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3); critical for the EFNA1-induced activation of RAC1 which stimulates cell migration (By similarity). Interacts with INPPL1; regulates activated EPHA2 endocytosis and degradation. Interacts (inactivated form) with PTK2/FAK1 and interacts (EFNA1 ligand-activated form) with PTPN11; regulates integrin-mediated adhesion. Interacts with ARHGEF16, DOCK4 and ELMO2; mediates ligand-independent activation of RAC1 which stimulates cell migration. Interacts with CLDN4; phosphorylates CLDN4 and may regulate tight junctions. Interacts with ACP1. Interacts (via SAM domain) with ANKS1A (via SAM domain). Interacts with CEMIP. Interacts with NCK1; may regulate EPHA2 activity in cell migration and adhesion. {ECO:0000250\|UniProtKB:Q03145, ECO:0000269\|PubMed:10655584, ECO:0000269\|PubMed:12167657, ECO:0000269\|PubMed:16236711, ECO:0000269\|PubMed:17135240, ECO:0000269\|PubMed:19525919, ECO:0000269\|PubMed:20505120, ECO:0000269\|PubMed:20679435, ECO:0000269\|PubMed:22332920, ECO:0000269\|PubMed:23358419, ECO:0000269\|PubMed:23936024}.
Subunit:		(Microbial infection) Interacts with human herpes virus 8/HHV- 8 glycoprotein L/gL and glycoprotein H/gH heterodimer; this interaction triggers EPHA2 phosphorylation and endocytosis, allowing virus entry. {ECO:0000269\|PubMed:22635007}.
Subunit:		(Microbial infection) Interacts with Epstein-Barr virus/HHV-4 glycoprotein L/gL and glycoprotein H/gH heterodimer; this interaction facilitates virus internalization and fusion. {ECO:0000269\|PubMed:29292383, ECO:0000269\|PubMed:29292384}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:18794797, ECO:0000269\|PubMed:19573808, ECO:0000269\|PubMed:20223987, ECO:0000269\|PubMed:20861311}; Single-pass type I membrane protein {ECO:0000255}. Cell projection, ruffle membrane {ECO:0000269\|PubMed:19573808}; Single-pass type I membrane protein {ECO:0000255}. Cell projection, lamellipodium membrane {ECO:0000269\|PubMed:19573808}; Single-pass type I membrane protein {ECO:0000255}. Cell junction, focal adhesion {ECO:0000269\|PubMed:10655584}. Note=Present at regions of cell-cell contacts but also at the leading edge of migrating cells (PubMed:19573808, PubMed:20861311). Relocates from the plasma membrane to the cytoplasmic and perinuclear regions in cancer cells (PubMed:18794797). {ECO:0000269\|PubMed:18794797, ECO:0000269\|PubMed:19573808, ECO:0000269\|PubMed:20861311, ECO:0000269\|PubMed:26158630}.
Tissue specificity:		Expressed in brain and glioma tissue and glioma cell lines (at protein level). Expressed most highly in tissues that contain a high proportion of epithelial cells, e.g. skin, intestine, lung, and ovary. {ECO:0000269\|PubMed:17332925}.
Induction:		Up-regulated by UV irradiation via a TP53-independent, MAPK- dependent mechanism. {ECO:0000269\|PubMed:18339848}.
Ptm:		Autophosphorylates. Phosphorylated on tyrosine upon binding and activation by EFNA1. Phosphorylated residues Tyr-588 and Tyr-594 are required for binding VAV2 and VAV3 while phosphorylated residues Tyr- 735 and Tyr-930 are required for binding PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3). These phosphorylated residues are critical for recruitment of VAV2 and VAV3 and PI3-kinase p85 subunit which transduce downstream signaling to activate RAC1 GTPase and cell migration. Dephosphorylation of Tyr-930 by PTPRF prevents the interaction of EPHA2 with NCK1. Phosphorylated at Ser-897 by PKB; serum-induced phosphorylation which targets EPHA2 to the cell leading edge and stimulates cell migration. Phosphorylation by PKB is inhibited by EFNA1-activated EPHA2 which regulates PKB activity via a reciprocal regulatory loop. Phosphorylated at Ser-897 in response to TNF by RPS6KA1 and RPS6KA3; RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630). Phosphorylated at Ser-897 by PKA; blocks cell retraction induced by EPHA2 kinase activity (PubMed:27385333). Dephosphorylated by ACP1. {ECO:0000269\|PubMed:10655584, ECO:0000269\|PubMed:18794797, ECO:0000269\|PubMed:19573808, ECO:0000269\|PubMed:23358419, ECO:0000269\|PubMed:26158630, ECO:0000269\|PubMed:27385333}.
Ptm:		Ubiquitinated by CHIP/STUB1. Ubiquitination is regulated by the HSP90 chaperone and regulates the receptor stability and activity through proteasomal degradation. ANKS1A prevents ubiquitination and degradation (By similarity). {ECO:0000250}.
Disease:		Cataract 6, multiple types (CTRCT6) [MIM:116600]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT6 includes posterior polar and age-related cortical cataracts, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. Age-related cortical cataract is a developmental punctate opacity restricted to the cortex. The cataract is white or cerulean, increases in number with age, but rarely affects vision. {ECO:0000269\|PubMed:19005574, ECO:0000269\|PubMed:19306328, ECO:0000269\|PubMed:19649315, ECO:0000269\|PubMed:22570727}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Note=Overexpressed in several cancer types and promotes malignancy. {ECO:0000269\|PubMed:19573808}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00159}.