Biology Reference
In-Depth Information
cells) support a model whereby bidirectional, repulsive signalling between
EphB4- and ephrin-B2-expressing cells leads to the segregation of these two
endothelial cell populations. This segregation appears to underlie the
separation of arteries and veins, which is crucial for the correct development
of the embryonic vasculature (Pandey et al., 1995; Wang et al., 1998; Adams
et al., 1999).
Interestingly, ephrins can also stimulate endothelial sprouting inducing the
assembly of capillary networks both in vitro and in vivo (Adams et al., 1999;
Stein et al., 1998; Wang et al., 1998). These findings suggest that a
combination of repulsive and attractive responses to Eph/ephrin signalling
in endothelial cells might regulate the assembly, branching and remodelling of
the primitive vascular network during embryogenesis.
Eph receptor/ephrin signalling
The exact nature of the cellular response underlying Eph receptor/ephrin
mediated regulation of axon pathfinding, tissue boundary formation,
vasculogenesis and angiogenesis is unknown. Cell-cell repulsion responses
suggest de-adhesion mechanisms whereby an Eph receptor expressing cell will
decrease its a
nity for, and thus detach from, its ephrin expressing neighbour.
Indeed, there is some evidence for ephrin-stimulated modulation of cell
adhesions in tissue culture cells expressing Eph receptors, although these are
cell-substrate adhesion effects rather than cell-cell adhesion effects (Huynh-
Do et al., 1999; Zou et al., 1999; Miao et al., 2000; Carter et al., 2002). The
collapse response of nerve growth cones to ephrins is proposed to be via
disassembly of actin structures and thus a loss of the dynamic protrusive actin
structures, filopodia and lamellipodia, required for growth cone migration
(Meima et al., 1997a,b).
Binding ephrins induces Eph receptors to form higher order clusters,
leading to receptor autophosphorylation on several intracellular tyrosine
residues. Like other receptor tyrosine kinases, activated Eph receptors can
recruit adaptor molecules including Nck, p85-PI3 kinase, Src and Grb2
(Kullander and Klein, 2002) although, to date, none of these adaptors has
been shown to be critically important.
Interestingly, in addition to phosphorylation-dependent recruitment of
signalling effectors in the receptor-expressing cells it has been shown that
B-class ephrins become phosphorylated on their intracellular tail following
Eph receptor/ephrin interaction (Holland et al., 1996; Bruckner et al., 1997).
One adaptor, recruited to ephrin-B1, is Grb4, which appears to trigger loss of
polymerized actin structures and the disassembly of focal adhesions (Cowan
and Henkemeyer, 2001).
