124
N. Holder et al.
outlines the evidence for these conclusions and focuses mainly, but not
exclusively, on the role of Eph/ephrin signalling in the nervous system.
Receptor tyrosine kinases (RTKs) are membrane-spanning proteins
with an extracellular ligand-binding domain and an intracellular kinase
domain. There are at least 14 subfamilies of RTKs (Van der Geer et al.
1994), and the Eph subfamily is the largest (Orioli and Klein 1997;
Pasquale 1997; Tuzi and Gullick 1994). Each subfamily has characteristic ligand-binding and kinase domains and is activated by a distinct
ligand or group of ligands. Many RTKs play roles in a broad range of
processes in development. In 1987, Hirai et al. described the cloning and
characterisation of the first member of the Eph subfamily, EphA 1 (Hirai
et al. 1987). To date as many as 14 genes have been described which are
related to Eph by sequence and by general characteristics of their kinase
and extracellular domains. Members of this subfamily of receptors have
been isolated and characterised in a range of vertebrate species, including human, mouse, rat, chicken, Xenopus and zebrafish. They have also
been isolated in invertebrates (George et al. 1998), but the invertebrate
genes have been studied much less intensively than their vertebrate
counterparts.
Ligands for the Eph family of RTKs, now known as ephrins (Eph
Nomenclature Committee 1997) were identified in 1994 (Bartley et al.
1994). The receptors are now termed EphA or B depending on the class
of ephrins that they bind (Eph Nomenclature Committee 1997; Table 1).
The ephrins (Pandey et al. 1995) can be grouped into two classes: those
which are connected to the membrane by a GPI linkage, called ephrin-A
proteins (which bind to EphA receptors) and those with membranespanning and intracellular domains, called ephrin-B proteins (which
bind to EphB receptors). The only receptor able to bind class A and class
B ephrins is EphA4 (Gale et al. 1996). Like the receptors, the ephrins are
dynamically expressed in the vertebrate embryo in various regions and
tissues in the forming mesoderm, endoderm and nervous system. It has
recently been shown that the transmembrane ligands, ephrin-B 1 and
-B2, can themselves become phosphorylated on their intracellular domains following binding and activation by receptors in an adjacent cell
(Bruckner et al. 1997; Holland et al. 1996). A further key feature of
ligand function is that they need to be membrane-bound to efficiently
cluster and activate receptor signalling (Davis et al. 1994). This means
that soluble forms of the ligands are likely to act as dominant-negative
N. Holder et al.
outlines the evidence for these conclusions and focuses mainly, but not
exclusively, on the role of Eph/ephrin signalling in the nervous system.
Receptor tyrosine kinases (RTKs) are membrane-spanning proteins
with an extracellular ligand-binding domain and an intracellular kinase
domain. There are at least 14 subfamilies of RTKs (Van der Geer et al.
1994), and the Eph subfamily is the largest (Orioli and Klein 1997;
Pasquale 1997; Tuzi and Gullick 1994). Each subfamily has characteristic ligand-binding and kinase domains and is activated by a distinct
ligand or group of ligands. Many RTKs play roles in a broad range of
processes in development. In 1987, Hirai et al. described the cloning and
characterisation of the first member of the Eph subfamily, EphA 1 (Hirai
et al. 1987). To date as many as 14 genes have been described which are
related to Eph by sequence and by general characteristics of their kinase
and extracellular domains. Members of this subfamily of receptors have
been isolated and characterised in a range of vertebrate species, including human, mouse, rat, chicken, Xenopus and zebrafish. They have also
been isolated in invertebrates (George et al. 1998), but the invertebrate
genes have been studied much less intensively than their vertebrate
counterparts.
Ligands for the Eph family of RTKs, now known as ephrins (Eph
Nomenclature Committee 1997) were identified in 1994 (Bartley et al.
1994). The receptors are now termed EphA or B depending on the class
of ephrins that they bind (Eph Nomenclature Committee 1997; Table 1).
The ephrins (Pandey et al. 1995) can be grouped into two classes: those
which are connected to the membrane by a GPI linkage, called ephrin-A
proteins (which bind to EphA receptors) and those with membranespanning and intracellular domains, called ephrin-B proteins (which
bind to EphB receptors). The only receptor able to bind class A and class
B ephrins is EphA4 (Gale et al. 1996). Like the receptors, the ephrins are
dynamically expressed in the vertebrate embryo in various regions and
tissues in the forming mesoderm, endoderm and nervous system. It has
recently been shown that the transmembrane ligands, ephrin-B 1 and
-B2, can themselves become phosphorylated on their intracellular domains following binding and activation by receptors in an adjacent cell
(Bruckner et al. 1997; Holland et al. 1996). A further key feature of
ligand function is that they need to be membrane-bound to efficiently
cluster and activate receptor signalling (Davis et al. 1994). This means
that soluble forms of the ligands are likely to act as dominant-negative