Stem Cells, Vol. 18, No. 1, 63-64,
January 2000
© 2000 AlphaMed Press
Fundamentals of Cancer Medicine |
Eph Receptors and Ephrins
Paige L. Jensen
R&D Systems, Inc., Minneapolis, Minnesota, USA
Paige L. Jensen, Ph.D., R&D Systems, Inc., 614 McKinley Place NE, Minneapolis, Minnesota, USA. Telephone: 612-379-2956; Fax: 612-379-6580; email:paigej{at}rndsystems.com
The Eph family of receptors is the largest known sub-family of receptor tyrosine kinases [1, 2]. The ligands are called ephrins. The ephrin-Eph interactions are important in development, especially in cell-cell interactions involved in nervous system patterning (axon guidance), angiogenesis, and possibly in cancer [1-5]. Prior to the adaptation of a common nomenclature, the receptors and ligands had multiple names [6]. Recent reviews on Eph receptors and ephrin ligands have been performed [3, 7, 8].
The Eph name is derived from the cell line from which the first member was isolated, erythropoietin-producing human hepatocellular carcinoma line [6]. Eph receptors have been divided into two groups, designated EphA and EphB, on the basis of sequence homology [9]. The extracellular region contains an Ig domain at the amino terminus, a cysteine-rich region, and two fibronectin type III repeats near a single membrane-spanning region. The cytoplasmic region contains a highly conserved tyrosine kinase domain flanked by a juxtamembrane region and a carboxy-terminal tail [3].
The Eph ligands are called ephrins, derived from an abbreviation for Eph family receptor interacting proteins [6]. They are cell-surface associated proteins, and they naturally divide into two groups, ephrin-A and ephrin-B, based on structure and function. Ephrin-As are anchored to the cell via a glycosylphosphatidylinositol (GPI) linkage [4, 6, 9], while ephrin-Bs are transmembrane proteins (Fig. 1) [4, 6, 9]. With few exceptions, EphA receptors bind ephrin-A and EphB receptors bind ephrin-B (Table 1
) [3, 4, 6]. In vitro, each Eph receptor can bind multiple ligands and each ligand can bind multiple receptors [1, 3, 9]. In vivo, the receptors and ligands display reciprocal expression [3] and may display less promiscuous binding [7, 8].
Ligand binding results in Eph autophosphorylation on tyrosine and activation of receptor tyrosine kinase activity [9]. Only membrane-bound or Fc-clustered ligands are capable of activating the receptor in vitro [9, 10]. While soluble monomeric ligands bind the receptor, they do not induce receptor autophosphorylation and activation [10]. Several signaling molecules bind via their SH2 domain to the phosphorylated Eph receptor [3]. Phosphatidylinositol 3-kinase activity is increased in response to EphA2 receptor activation [3]. Ephrin-B ligands are also phosphorylated by an unidentified kinase upon binding the EphB receptor [3, 11]. The phosphorylated ephrin-B ligand can presumably interact with cellular signaling molecules [3, 11], providing a mechanism of bi-directional cell-cell signaling. However, detailed signaling pathways for the Eph receptors and ephrin-B ligands have not been elucidated.
Fc-clustered soluble ligand can cause the growth cones of cultured temporal retinal neurons, bearing the appropriate Eph receptor, to collapse [3]. The collapse of the growth cone is accompanied by disruption of the actin cytoskeleton within the growth cone [3, 12]. In Xenopus, ectopic expression of activated EphA4 resulted in decreased cell-cell adhesion. This decrease in cell-cell adhesion was possibly due to an effect on the function of cadherin [3, 13]. Additional observations suggest that Eph receptor-mediated cell-cell recognition can result in the nullification of cell-cell adhesion mechanisms [3]. Many cancers display overexpression of Eph receptors and/or ephrin ligands, possibly resulting in downregulation of cell adhesion when the Eph receptor and/or ephrin ligand on the tumor cell encounters the other on adjacent cells. This may then play a role in cancer metastasis [3].
References
-
Drescher U. The Eph family in the patterning of neural development. Curr Biol 1997;7:R799-R807.[CrossRef][Medline]
-
Tuzi NL, Gullick WJ. eph, the largest known family of putative growth factor receptors. Br J Cancer 1994;69:417-421.[Medline]
-
Pasquale EB. The Eph family of receptors. Curr Opin Cell Biol 1997;9:608-615.[CrossRef][Medline]
-
Pandey A, Lindberg RA, Dixit VM. Cell signalling. Receptor orphans find a family. Curr Biol 1995;5:986-989.[CrossRef][Medline]
-
Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 1998;93:741-753.[CrossRef][Medline]
-
Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee (letter). Cell 1997;90:403-404.[CrossRef][Medline]
-
O'Leary DD, Wilkinson DG. Eph receptors and ephrins in neural development. Curr Opin Neurobiol 1999;9:65-73.[CrossRef][Medline]
-
Bruckner K, Klein R. Signaling by Eph receptors and their ephrin ligands. Curr Opin Neurobiol 1998;8:375-382.[CrossRef][Medline]
-
Gale NW et al. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 1996;17:9-19.[CrossRef][Medline]
-
Davis S et al. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 1994;266:816-819.[Abstract/Free Full Text]
-
Holland SJ et al. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 1996;383:722-725.[CrossRef][Medline]
-
Meima L et al. AL-1-induced growth cone collapse of rat cortical neurons is correlated with REK7 expression and rearrangement of the actin cytoskeleton. Eur J Neurosci 1997;9:177-188.[CrossRef][Medline]
-
Winning RS, Scales JB, Sargent TD. Disruption of cell adhesion in Xenopus embryos by Pagliaccio, an Eph-class receptor tyrosine kinase. Dev Biol 1996;179:309-319.[CrossRef][Medline]
-
Flanagan JG, Vanderhaeghen P. The ephrins and Eph receptors in neural development. Annu Rev Neurosci 1998;21:309-345.[CrossRef][Medline]
