Note | EphA1 was isolated originally from an erythropoietin producing hepatoma cell line, from which its name, and the name of its gene family, derives. |
| |
|  |
| |
| Domain organisation of EphA1. |
| |
Description | The EPHA1 gene encodes a 976 amino acid protein with a calculated molecular weight of 108,126.89 and an isoelectric point of 6.6254. Amino acids 1-25 constitute a signal peptide. EphA1 is the founding member of what is recognised as the largest subfamily of the receptor tyrosine kinases. This is an evolutionarily ancient protein group with members being present in sponges, worms and fruit flies. The expansion in the number of Eph receptor-encoding genes along with genes encoding their ligands, the ephrins (Eph receptor interacting proteins), is proposed to have contributed to the increase in complexity of the bilaterian body plan. Fourteen Eph receptors have been identified in vertebrates. These are subdivided into either EphA (EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphA10) or EphB ( EphB1, EphB2, EphB3, EphB4, EphB6) subclasses which differ primarily in the structure of their ligand binding domains. EphA receptors also exhibit greater affinity for binding GPI-linked ephrin-A ligands while EphB receptors bind transmembrane ephrin-B ligands. While interactions are somewhat promiscuous, and some cross-class binding occurs, each Eph receptor displays distinct affinity for the different ephrin ligands. Eph-ephrin binding involves cell-cell contact. Upon binding, both Eph and ephrin proteins on respective cells dimerise, and undergo higher order clustering. This results in signalling within both the Eph- and ephrin-bearing cells (bidirectional signalling) and either subsequent adhesion or repulsion of the interacting cells. Cell-cell contact, and thus Eph-ephrin signalling, may be terminated either by enzymatic cleavage of the extracellular domain of the Eph receptor or ephrin ligand or endocytosis of Eph-ephrin complexes. The high affinity ligands for EphA1 are ephrin-A1 and ephrin-A3. EphA1 also binds fibronectin, a non-activating ligand. |
Expression | Embryonic stem (ES) cells and embryoid bodies differentiated from ES cells in vitro; dynamic and regionalised expression during murine embryogenesis (including epiblast, primitive streak, paraxial mesoderm, tail bud mesoderm, distal limb bud); human lung, small intestinal, kidney, bladder, thymus, skin and colon. Murine adult epithelial tissues (including epidermis of skin and vagina, endometrium, renal collecting system). Rat normal liver, kidney, lung. Human tumours and cell lines of epithelial origin. |
Localisation | Membrane; single-pass type I membrane protein. |
Function | Not yet entirely established. Generally repulsive interaction with its high affinity ligands ephrin-A1 and ephrin-A3. Transgenic expression of EphA1 in the blastula of pre-implantation mice is lethal (Duffy et al., unpublished). EphA1 homozygous null mice exhibit kinked tails (80%) and imperforate vagina (18% of females). The apparent absence of EphA1 in fish (zebrafish, medaka, fugu) and amphibia (Xenopus) and its emergence in vertebrates with reptiles (anole lizard) and birds (chicken) hints at an association with the transition of life from an aquatic to terrestrial environment. The presence of a membrane-embedded ionogenic Glu547 residue within the transmembrane domain of EphA1 also is unique among the Eph receptors. The structural-dynamic properties of the transmembrane domain have been shown to be dependent on the ionisation state of this residue, a finding that implies that the conformational flexibility and activation of the EphA1 receptor can be regulated by such external and local factors as pH and lipid composition of the membrane, a finding which may be of particular relevance to EphA1 function in the skin and kidney. |
|  |
| |
Homology | Phylogenetic tree for the Eph receptors. Amino acid sequences used for this compilation were EphA1 (NP_005223), EphA2 (NM_004431), EphA3 (NP_005224), EphA4 (NP_004429), EphA5 (NM_004439), EphA6 (ENSP00000374323), EphA7 (NP_004431), EphA8 (NP_065387), EphA10 (NP_001092909), EphB1 (NP_004432), EphB2 (NP_004433), EphB3 (NP_004434), EphB4 (NP_004435) and EphB6 (NP_004436). |
Approximate likelihood-ratio test for branches: A fast, accurate, and powerful alternative. |
Anisimova M, Gascuel O. |
Syst Biol. 2006 Aug;55(4):539-52. |
PMID 16785212 |
|
Spatial structure and pH-dependent conformational diversity of dimeric transmembrane domain of the receptor tyrosine kinase EphA1. |
Bocharov EV, Mayzel ML, Volynsky PE, Goncharuk MV, Ermolyuk YS, Schulga AA, Artemenko EO, Efremov RG, Arseniev AS. |
J Biol Chem. 2008 Oct 24;283(43):29385-95. Epub 2008 Aug 26. |
PMID 18728013 |
|
Signals from Eph and ephrin proteins: a developmental tool kit. |
Boyd AW, Lackmann M. |
Sci STKE. 2001 Dec 11;2001(112):RE20. |
PMID 11741094 |
|
Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis. |
Castresana J. |
Mol Biol Evol. 2000 Apr;17(4):540-52. |
PMID 10742046 |
|
TreeDyn: towards dynamic graphics and annotations for analyses of trees. |
Chevenet F, Brun C, Banuls AL, Jacq B, Christen R. |
BMC Bioinformatics. 2006 Oct 10;7:439. |
PMID 17032440 |
|
Characterization of the Epha1 receptor tyrosine kinase: expression in epithelial tissues. |
Coulthard MG, Lickliter JD, Subanesan N, Chen K, Webb GC, Lowry AJ, Koblar S, Bottema CD, Boyd AW. |
Growth Factors. 2001;18(4):303-17. |
PMID 11519828 |
|
Phylogeny.fr: robust phylogenetic analysis for the non-specialist. |
Dereeper A, Guignon V, Blanc G, Audic S, Buffet S, Chevenet F, Dufayard JF, Guindon S, Lefort V, Lescot M, Claverie JM, Gascuel O. |
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W465-9. Epub 2008 Apr 19. |
PMID 18424797 |
|
Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis. |
Dong Y, Wang J, Sheng Z, Li G, Ma H, Wang X, Zhang R, Lu G, Hu Q, Sugimura H, Zhou X. |
Mod Pathol. 2009 Jan;22(1):151-60. Epub 2008 Nov 14. |
PMID 19011600 |
|
Eph family functions from an evolutionary perspective. |
Drescher U. |
Curr Opin Genet Dev. 2002 Aug;12(4):397-402. |
PMID 12100883 |
|
Generation and characterization of EphA1 receptor tyrosine kinase reporter knockout mice. |
Duffy SL, Coulthard MG, Spanevello MD, Herath NI, Yeadon TM, McCarron JK, Carter JC, Tonks ID, Kay GF, Phillips GE, Boyd AW. |
Genesis. 2008 Oct;46(10):553-61. |
PMID 18802966 |
|
Expression analysis of the Epha1 receptor tyrosine kinase and its high-affinity ligands Efna1 and Efna3 during early mouse development. |
Duffy SL, Steiner KA, Tam PP, Boyd AW. |
Gene Expr Patterns. 2006 Oct;6(7):719-23. Epub 2006 Feb 8. |
PMID 16466970 |
|
MUSCLE: multiple sequence alignment with high accuracy and high throughput. |
Edgar RC. |
Nucleic Acids Res. 2004 Mar 19;32(5):1792-7. Print 2004. |
PMID 15034147 |
|
Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. |
Fox BP, Kandpal RP. |
Biochem Biophys Res Commun. 2004 Jun 11;318(4):882-92. |
PMID 15147954 |
|
Potential clinical relevance of Eph receptors and ephrin ligands expressed in prostate carcinoma cell lines. |
Fox BP, Tabone CJ, Kandpal RP. |
Biochem Biophys Res Commun. 2006 Apr 21;342(4):1263-72. Epub 2006 Feb 28. |
PMID 16516143 |
|
A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. |
Guindon S, Gascuel O. |
Syst Biol. 2003 Oct;52(5):696-704. |
PMID 14530136 |
|
Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. |
Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T, Dietmaier W, Landthaler M, Vogt T. |
Clin Chem. 2004 Mar;50(3):490-9. Epub 2004 Jan 15. |
PMID 14726470 |
|
Over-expression of Eph and ephrin genes in advanced ovarian cancer: ephrin gene expression correlates with shortened survival. |
Herath NI, Spanevello MD, Sabesan S, Newton T, Cummings M, Duffy S, Lincoln D, Boyle G, Parsons PG, Boyd AW. |
BMC Cancer. 2006 Jun 1;6:144. |
PMID 16737551 |
|
A novel putative tyrosine kinase receptor encoded by the eph gene. |
Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F. |
Science. 1987 Dec 18;238(4834):1717-20. |
PMID 2825356 |
|
Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis. |
Jin P, Zhang J, Sumariwalla PF, Ni I, Jorgensen B, Crawford D, Phillips S, Feldmann M, Shepard HM, Paleolog EM. |
Arthritis Res Ther. 2008;10(4):R73. Epub 2008 Jul 1. |
PMID 18593464 |
|
Identification of tyrosine kinases overexpressed in head and neck cancer. |
Lin HS, Berry GJ, Fee WE Jr, Terris DJ, Sun Z. |
Arch Otolaryngol Head Neck Surg. 2004 Mar;130(3):311-6. |
PMID 15023838 |
|
Overexpression confers an oncogenic potential upon the eph gene. |
Maru Y, Hirai H, Takaku F. |
Oncogene. 1990 Mar;5(3):445-7. |
PMID 2314900 |
|
Fibronectin type I repeat is a nonactivating ligand for EphA1 and inhibits ATF3-dependent angiogenesis. |
Masuda J, Usui R, Maru Y. |
J Biol Chem. 2008 May 9;283(19):13148-55. Epub 2008 Feb 28. |
PMID 18308734 |
|
Genomic structure of the EPHA1 receptor tyrosine kinase gene. |
Owshalimpur D, Kelley MJ. |
Mol Cell Probes. 1999 Jun;13(3):169-73. |
PMID 10369740 |
|
Eph-ephrin bidirectional signaling in physiology and disease. |
Pasquale EB. |
Cell. 2008 Apr 4;133(1):38-52. |
PMID 18394988 |
|
A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. |
Stephens P, Edkins S, Davies H, Greenman C, Cox C, Hunter C, Bignell G, Teague J, Smith R, Stevens C, O'Meara S, Parker A, Tarpey P, Avis T, Barthorpe A, Brackenbury L, Buck G, Butler A, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Green A, Knowles M, Leung SY, Looijenga LH, Malkowicz B, Pierotti MA, Teh B, Yuen ST, Nicholson AG, Lakhani S, Easton DF, Weber BL, Stratton MR, Futreal PA, Wooster R. |
Nat Genet. 2005 Jun;37(6):590-2. Epub 2005 May 22. |
PMID 15908952 |
|