EPHA2_MACFA
ID EPHA2_MACFA Reviewed; 976 AA.
AC Q1KL86;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2006, sequence version 1.
DT 03-AUG-2022, entry version 102.
DE RecName: Full=Ephrin type-A receptor 2;
DE EC=2.7.10.1;
DE Flags: Precursor;
GN Name=EPHA2;
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Skin;
RA Walsh W.D., Bruckheimer E.M.;
RT "Macaca fascicularis EPH receptor A2 (EPHA2).";
RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Receptor tyrosine kinase which binds promiscuously membrane-
CC bound ephrin-A family ligands residing on adjacent cells, leading to
CC contact-dependent bidirectional signaling into neighboring cells. The
CC signaling pathway downstream of the receptor is referred to as forward
CC signaling while the signaling pathway downstream of the ephrin ligand
CC is referred to as reverse signaling. Activated by the ligand ephrin-
CC A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation
CC and differentiation of cells. Regulates cell adhesion and
CC differentiation through DSG1/desmoglein-1 and inhibition of the
CC ERK1/ERK2 signaling pathway. May also participate in UV radiation-
CC induced apoptosis and have a ligand-independent stimulatory effect on
CC chemotactic cell migration. During development, may function in
CC distinctive aspects of pattern formation and subsequently in
CC development of several fetal tissues. Involved for instance in
CC angiogenesis, in early hindbrain development and epithelial
CC proliferation and branching morphogenesis during mammary gland
CC development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens
CC fiber cells shape and interactions and be important for lens
CC transparency development and maintenance. With ephrin-A2/EFNA2 may play
CC a role in bone remodeling through regulation of osteoclastogenesis and
CC osteoblastogenesis (By similarity). {ECO:0000250|UniProtKB:P29317}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- SUBUNIT: Homodimer. Interacts with SLA. Interacts (phosphorylated form)
CC with VAV2, VAV3 and PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3);
CC critical for the EFNA1-induced activation of RAC1 which stimulates cell
CC migration. Interacts with INPPL1; regulates activated EPHA2 endocytosis
CC and degradation. Interacts (inactivated form) with PTK2/FAK1 and
CC interacts (EFNA1 ligand-activated form) with PTPN11; regulates
CC integrin-mediated adhesion. Interacts with ARHGEF16, DOCK4 and ELMO2;
CC mediates ligand-independent activation of RAC1 which stimulates cell
CC migration. Interacts with CLDN4; phosphorylates CLDN4 and may regulate
CC tight junctions. Interacts with ACP1. Interacts with ANKS1A. Interacts
CC with CEMIP. Interacts with NCK1; may regulate EPHA2 activity in cell
CC migration and adhesion.Interacts with TIMD4 (By similarity).
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P29317};
CC Single-pass type I membrane protein {ECO:0000255}. Cell projection,
CC ruffle membrane {ECO:0000250|UniProtKB:P29317}; Single-pass type I
CC membrane protein {ECO:0000255}. Cell projection, lamellipodium membrane
CC {ECO:0000250|UniProtKB:P29317}; Single-pass type I membrane protein
CC {ECO:0000255}. Cell junction, focal adhesion
CC {ECO:0000250|UniProtKB:P29317}. Note=Present at regions of cell-cell
CC contacts but also at the leading edge of migrating cells. Relocates
CC from the plasma membrane to the cytoplasmic and perinuclear regions in
CC cancer cells. {ECO:0000250|UniProtKB:P29317}.
CC -!- PTM: Autophosphorylates. Phosphorylated on tyrosine upon binding and
CC activation by EFNA1. Phosphorylated residues Tyr-588 and Tyr-594 are
CC required for binding VAV2 and VAV3 while phosphorylated residues Tyr-
CC 735 and Tyr-930 are required for binding PI3-kinase p85 subunit
CC (PIK3R1, PIK3R2 or PIK3R3). These phosphorylated residues are critical
CC for recruitment of VAV2 and VAV3 and PI3-kinase p85 subunit which
CC transduce downstream signaling to activate RAC1 GTPase and cell
CC migration. Dephosphorylation of Tyr-930 by PTPRF prevents the
CC interaction of EPHA2 with NCK1. Phosphorylated at Ser-897 by PKB;
CC serum-induced phosphorylation which targets EPHA2 to the cell leading
CC edge and stimulates cell migration. Phosphorylation by PKB is inhibited
CC by EFNA1-activated EPHA2 which regulates PKB activity via a reciprocal
CC regulatory loop. Phosphorylated at Ser-897 in response to TNF by
CC RPS6KA1 and RPS6KA3; RPS6KA-EPHA2 signaling pathway controls cell
CC migration. Phosphorylated at Ser-897 by PKA; blocks cell retraction
CC induced by EPHA2 kinase activity. Dephosphorylated by ACP1.
CC {ECO:0000250|UniProtKB:P29317, ECO:0000250|UniProtKB:Q03145}.
CC -!- PTM: Ubiquitinated by CHIP/STUB1. Ubiquitination is regulated by the
CC HSP90 chaperone and regulates the receptor stability and activity
CC through proteasomal degradation. ANKS1A prevents ubiquitination and
CC degradation (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Ephrin receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; DQ478608; ABE96827.1; -; mRNA.
DR RefSeq; NP_001306345.1; NM_001319416.1.
DR AlphaFoldDB; Q1KL86; -.
DR SMR; Q1KL86; -.
DR STRING; 9541.XP_005544739.1; -.
DR GeneID; 102146108; -.
DR CTD; 1969; -.
DR eggNOG; KOG0196; Eukaryota.
DR Proteomes; UP000233100; Unplaced.
DR GO; GO:0005925; C:focal adhesion; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0030027; C:lamellipodium; ISS:UniProtKB.
DR GO; GO:0031258; C:lamellipodium membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031256; C:leading edge membrane; ISS:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005003; F:ephrin receptor activity; IEA:InterPro.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; ISS:UniProtKB.
DR GO; GO:0090630; P:activation of GTPase activity; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0046849; P:bone remodeling; ISS:UniProtKB.
DR GO; GO:0060444; P:branching involved in mammary gland duct morphogenesis; ISS:UniProtKB.
DR GO; GO:0046058; P:cAMP metabolic process; ISS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0060326; P:cell chemotaxis; ISS:UniProtKB.
DR GO; GO:0016477; P:cell migration; ISS:UniProtKB.
DR GO; GO:0048870; P:cell motility; ISS:UniProtKB.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0070309; P:lens fiber cell morphogenesis; ISS:UniProtKB.
DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; ISS:UniProtKB.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0001649; P:osteoblast differentiation; ISS:UniProtKB.
DR GO; GO:0030316; P:osteoclast differentiation; ISS:UniProtKB.
DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0045765; P:regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:0033628; P:regulation of cell adhesion mediated by integrin; ISS:UniProtKB.
DR GO; GO:0010591; P:regulation of lamellipodium assembly; ISS:UniProtKB.
DR GO; GO:0070848; P:response to growth factor; ISS:UniProtKB.
DR CDD; cd10480; EphR_LBD_A2; 1.
DR CDD; cd00063; FN3; 2.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR027936; Eph_TM.
DR InterPro; IPR034263; EphA2_rcpt_lig-bd.
DR InterPro; IPR001090; Ephrin_rcpt_lig-bd_dom.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR008979; Galactose-bd-like_sf.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016257; Tyr_kinase_ephrin_rcpt.
DR InterPro; IPR001426; Tyr_kinase_rcpt_V_CS.
DR Pfam; PF14575; EphA2_TM; 1.
DR Pfam; PF01404; Ephrin_lbd; 1.
DR Pfam; PF00041; fn3; 2.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF00536; SAM_1; 1.
DR PIRSF; PIRSF000666; TyrPK_ephrin_receptor; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00615; EPH_lbd; 1.
DR SMART; SM00060; FN3; 2.
DR SMART; SM00454; SAM; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR SUPFAM; SSF49265; SSF49265; 1.
DR SUPFAM; SSF49785; SSF49785; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS51550; EPH_LBD; 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00790; RECEPTOR_TYR_KIN_V_1; 1.
DR PROSITE; PS00791; RECEPTOR_TYR_KIN_V_2; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
PE 2: Evidence at transcript level;
KW Angiogenesis; Apoptosis; ATP-binding; Cell adhesion; Cell junction;
KW Cell membrane; Cell projection; Differentiation; Disulfide bond;
KW Glycoprotein; Kinase; Membrane; Nucleotide-binding; Phosphoprotein;
KW Receptor; Reference proteome; Repeat; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT CHAIN 24..976
FT /note="Ephrin type-A receptor 2"
FT /id="PRO_0000260316"
FT TOPO_DOM 25..537
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 538..558
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 559..976
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 28..206
FT /note="Eph LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00883"
FT DOMAIN 328..432
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 438..529
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 613..875
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 904..968
FT /note="SAM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT REGION 1..206
FT /note="Mediates interaction with CLDN4"
FT /evidence="ECO:0000250"
FT REGION 606..906
FT /note="Mediates interaction with ARHGEF16"
FT /evidence="ECO:0000250"
FT REGION 886..976
FT /note="Negatively regulates interaction with ARHGEF16"
FT /evidence="ECO:0000250"
FT MOTIF 974..976
FT /note="PDZ-binding"
FT /evidence="ECO:0000255"
FT ACT_SITE 739
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 619..627
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 646
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 570
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 575
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 579
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 588
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 594
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q03145"
FT MOD_RES 628
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 647
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 735
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q03145"
FT MOD_RES 772
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q03145"
FT MOD_RES 869
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 892
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 897
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 901
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT MOD_RES 921
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000255"
FT MOD_RES 930
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P29317"
FT CARBOHYD 407
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 435
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 70..188
FT /evidence="ECO:0000250"
FT DISULFID 105..115
FT /evidence="ECO:0000250"
SQ SEQUENCE 976 AA; 108506 MW; 244DD74D78F14EFB CRC64;
MELWAARACF VLLWGCALAP ATAAQGKEVV LLDFAAAGGE LGWLTHPYGK GWDLMQNIMN
DMPIYMYSVC NVMSGDQDNW LRTNWVYRGE AERIFIELKF TVRDCNSFPG GASSCKETFN
LYYAESDLDY GTNFQKRLFT KIDTIAPDEI TVSSDFEARH VKLNVEERSV GPLTRKGFYL
AFQDIGACVA LLSVRVYYKK CPELLQSLAR FPETIAGSDA PSLATVAGTC VDHAVVPPGG
EEPRMHCAVD GEWLVPIGQC LCQAGYEKVE DACQACSPGF FKFEVSESPC LECPEHTLPS
PEGATSCECE EGFFRAPQDP MSMPCTRPPS APHYLTAVGM GAKVELRWTP PQDSGGREDI
VYSVTCEQCW PESGECGPCE SSVRYSEPPH GLTRTSVTVS DLEPHMNYTF TVEARNGVSG
LVTSRSFRTA SVSINQTEPP KVRLEGRSTT SLSVSWSIPP PQQSRVWKYE VTYRKKGDSN
SYNVRRTEGF SVTLDDLAPD TTYLVQVQAL TQEGQGAGSK VHEFQTLSPE GSGSLAVIGG
VAVCVVLLLL LAGAGFFIHR RRKNLRARQS PEDVYFSKSE QLKPLKTYVD PHTYEDPNQA
VLKFTTEIHP SCVTRQKVIG AGEFGEVYKG TLKTSSGKKE VPVAIKTLKA GYTEKQRVDF
LGEAGIMGQF SHHNIIRLEG VISKYKPMMI ITEFMENGAL DKFLREKDGE FSVLQLVGML
RGIAAGMKYL ANMNYVHRDL AARNILVNSN LVCKVSDFGL SRVLEDDPEA TYTTSGGKIP
IRWTAPEAIS YRKFTSASDV WSFGIVMWEV MTYGERPYWE LSNHEVMKAI NDGFRLPTPM
DCPSAIYQLM MQCWQQERAR RPKFADIVSI LDKLIRAPDS LKTLADFDPR VSIRLPSTSG
SEGVPFRTVS EWLESIKMQQ YTEHFMAAGY TAIEKVVQMT NDDIKRIGVR LPGHQKRIAY
SLLGLKDQVN TVGIPI
