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of ephrin-A and EphA in the same subdomains by exchanging their ectodomains resulted in mutual interference in cis of the two types of proteins, and inhibited their signaling.72 In fact, the same cis inhibition of EphA signaling by ephrin-A114 can be invoked in order to attribute the ephrin-mediated increase in integrin-dependent cell adhesion to a relative increase in ephrin-A versus EphA signaling.115
Since Eph receptor-induced cell repulsion initially requires cell-to-cell contact, the trans interaction between Eph receptors and their ephrin ligands on the surfaces of opposing cells could hinder the repellant effects of Eph signaling. There are two known ways in which cells overcome this obstacle — either by trans-endocytosis, or by proteolytic cleavage of the ephrin ectodomain. EphB-receptor/ephrin-B complexes are engulfed by the EphB-presenting endothelial cells and fibroblasts in a process requiring Rac-dependent membrane ruffling which is not clathrinor caveolin-dependent.116 A concurrent study using fibroblasts and neurons detected bidirectional endocytosis of the full-length Eph receptor bound to full-length ephrin-B ligand into either host cell.117 Removal of the EphA receptor/ephrin-A complex was first thought to occur via proteolytic cleavage by the ADAM10 metalloprotease which cleaves only EphA-bound ephrin-A ligand in cis . A subsequent study found, however, that ADAM10 associated with Eph receptors cleaves ephrin-A in trans.118
Unrelated to the endocytic removal of Eph-ephrin complexes EphB-ephrin-B signaling regulates clathrin-dependent endocytosis. EphB stimulated by ephrin-B inactivates the phosphatidylinositol 5’- phosphatase synaptojanin 1 and disrupts its association with endophilin by tyrosine phosphorylation. The dissociation from endophilin uncouples synaptojanin from the endocytic machinery, and together with the inhibition of its catalytic activity, downregulates clathrin-dependent endocytosis. It is not known, however, how this downregulation contributes to EphB receptor-induced cell repulsion.
4. Netrin and Slit Signaling
Netrins are a family of secreted proteins related to the extracellular matrix protein laminin. Similar to other guidance cues, it has been
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initially studied in the neural system (reviewed in Ref.119). Recent studies implicated netrin and one of its known receptors, uncoordinated 5b (Unc5b) in angiogenesis and in the development of the vascular system.120−123 Unc5b, one of the four-member Unc5 family which is related to the Ig superfamily, is selectively expressed in the vascular system, including in endothelial tip cells.120−123 Unlike other netrin receptors, Unc5b receptors transduce only repellant signals. Netrin binding to the second Ig domain of Unc5b relieves the autoinhibitory effect of this domain124 and induces phosphorylation of Tyr482.125 The signaling pathway downstream of Unc5b has not been charted yet.
Deletion of Unc5b expression in the mouse and zebrafish caused aberrant growth of arterial branches, suggesting that netrin signaling via Unc5b is required for regulating the shape of the arterial tree.126 At the cellular level, netrin suppressed endothelial cell migration and retracted the filopodia of tip cells of growing capillaries. These results contrasted with a previous study which reported that netrin-1 is a proangiogenic factor.123 Further studies from the same group consistently showed that the effects of netrin-1 and -4 did not inhibit but rather promoted the formation of the vascular network in zebrafish and neovascularization in a mouse hindlimb ischemia model.121 Surprisingly, none of the known netrin receptors, including Unc5b, were expressed at significant levels in the endothelial cell systems that responded to netrins, and netrin-4 did not bind to any of these receptors. To date, the discrepancy between the results of these two recent studies have not been resolved.
Mammalian slit is a family of secreted proteins consisting of four members that are composed of multiple EGF and leucine-rich domains (reviewed in Ref.127). They bind to roundabout (Robo), a four-member transmembrane receptor family composed of extracellular Ig and fibronectin type III motifs, and of conserved cytoplasmic (CC) domains. The significance of Robo to vascular morphogenesis was initially suggested by the discovery of an endothelial-specific member, Robo4.128,129 The initial results suggested that Robo4 transmits repulsive signals, since endothelial cell migration was inhibited by slit.129 Similar to other guidance cues, however, the nature of slit/Robo4 signaling was put in question by subsequent studies which found that slit stimulated
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endothelial cell migration and in vitro tube formation.130 Furthermore, the actual identity of the Robo4 ligand has been questioned, since Robo4 is activated even when its amino-terminal Ig domain has been deleted,131 and since unlike Robo4, slits are not expressed during embryonic development. In vivo studies in zebrafish indicated that Robo signaling is essential for the development of the vascular system since Robo4 knock-down caused defective sprouting and loss of intersomitic vessels.132 An extension of these studies133 showed that the migration of single angioblasts from zebrafish in which Robo4 expression was knocked down was more random than that of WT angioblasts.
Robo4 signaling in porcine aortic endothelial cells modulated the actin cytoskeleton by activating the Rho-GTPases Rac1 and Cdc42, and by inducing lamellipodia and filopodia.133 These effects were fully or partially lost when cells were transfected with Robo4 mutants lacking the ectoplasmic domain, or both of the two CC domains, suggesting that ligand binding to the ectoplasmic domain and interactions of cellular proteins with the cytoplasmic domain are both required for Robo4 signaling. Transfection with Robo4 mutants that were unable to activate Rac1 and Cdc42 led to slower migration and reduced adhesion to fibronectin-coated substrate.
5. Open Questions
To a varying degree, the downstream signaling pathways of the guidance cues discussed here have been partially determined. There are still numerous knowledge gaps that need to be closed, and several contradictory findings that need to be reconciled.
The signaling downstream of plexD1 is particularly relevant to the morphogenesis of the vascular system, yet nothing is known to date concerning the immediate effectors. One intriguing aspect of plexD1 signaling is that it involves neuropilin when responding to sema3C, but not when responding to sema3E. There are several studies which have shown that neuropilin is endocytosed, but the mechanism of the endocytosis and its functional significance have not been determined. An attractive venue of investigation is the interaction of neuropilin with the PDZ domain protein synectin, which is an adaptor of the unconventional
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myosin VI.134 Unlike the case of Eph-ephrin signaling, little is known about the reverse signaling via the membrane-bound semaphorins. Similarly, it is still not known how the interaction between plexin receptors in trans with membrane-bound semaphorin on apposing cells is terminated, allowing the cells to detach from each other.
A general question concerning Eph-ephrin signaling is the significance of cis, the interaction between membrane-bound receptor and the ligand e.g. Eph and ephrin. Resolution of this issue is of special interest for the signaling of ephrin-B2 when activated by kinase-dead EphB4, both of which are involved in vascular morphogenesis.
Two major issues still need to be resolved in netrin and Robo4 signaling. There are conflicting studies claiming that either netrin or Robo4 signaling is either repulsive or attractive, but no mechanism has been proposed for reversing the nature of the signaling, as in the case of semaphorin. Unc5b, the receptor thought to transduce netrin signaling in the vascular system is not expressed in several endothelial cell types that are responsive to netrin, suggesting there are more still unidentified netrin receptors. Similarly, Robo4 is likely to have ligands other than the currently known three slit isoforms, since its ligand binding site is different from the other Robo receptors.
Finally, the spatial and temporal patterns of Rho-GTPase activity downstream of the directional cue receptors reviewed here are still poorly known.
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