The Ephs and Ephrins

The Eph family of RTKs comprise 15 members. They are activated by ligands, the ephrins (of which there are 9), which are cell surface bound. This system functions in short-range cell-to-cell communication. The ephrins are

Figure 2 FGFR-1 Signaling in the Endothelium. This schematic figure shows the main tyrosine phosphorylation sites in FGFR-1. Shaded boxes in the intracellular portion of the receptor denote the kinase domain. Signaling intermediates are shown adjacent to phosphotyrosine residues to which they bind. The adaptor protein FRS2 may be constitutively associated with the juxtamembrane region of FGFR-1. Maximal phosphorylation of FRS2 requires binding of Shb to pY766. Shp2 has been found to be constitutively associated with Shb and may act to link Shb with FRS2 phosphorylation. The pathways shown are those for which clear evidence exists in endothelial cells.

Figure 2 FGFR-1 Signaling in the Endothelium. This schematic figure shows the main tyrosine phosphorylation sites in FGFR-1. Shaded boxes in the intracellular portion of the receptor denote the kinase domain. Signaling intermediates are shown adjacent to phosphotyrosine residues to which they bind. The adaptor protein FRS2 may be constitutively associated with the juxtamembrane region of FGFR-1. Maximal phosphorylation of FRS2 requires binding of Shb to pY766. Shp2 has been found to be constitutively associated with Shb and may act to link Shb with FRS2 phosphorylation. The pathways shown are those for which clear evidence exists in endothelial cells.

divided into two subtypes: (1) those bound to the cell surface by glycosylphosphatidyl inositol (GPI) linkages, class A ephrins, and (2) those with transmembrane domains, class B ephrins. Two subtypes of Eph have also been defined, generally EphAs bind class A ephrins and EphBs class B ephrins. EphB2, EphB3, and EphB4 as well as the ligands ephrinBl and ephrinB2 have been implicated in microvessel formation. Transgenic mice deficient in EphB4 or ephrinB2 have defects in vasculogenesis and compromised angio-genic remodeling. Deficiency of EphB2 and EphB3 also results in defective vessel remodeling, although because of some functional compensation, the single knockouts do not have a defective vascular phenotype. These phenotypes are consistent with the known involvement of the Eph/ephrin system in regulating cellular repulsion, adhesion, and migration. The broadly reciprocal expression of EphB4 in venous endothelium and its ligand ephrinB2 in arterial endothelium suggest involvement in suppression of mixing between the two cell types, again in accord with roles in regulation of adhesive and repulsive interactions.

The Eph receptors all possess a glycosylated extracellular region consisting of an N-terminally located ligand-binding site, a cysteine-rich domain, and a dimerization motif contained within two fibronectin Ill-like repeats. The intracellular region follows the single transmembrane spanning domain and consists of a juxtamembrane region and a single tyrosine kinase domain, each of which contain tyrosines that when phosphorylated act as docking sites for downstream signaling molecules. The C-terminus has a PDZ binding motif to which PDZ motif containing proteins bind. These may act as scaffolds for the assembly of multiprotein signaling complexes at the membrane. There is a sterile alpha motif (SAM) domain just before the C-terminus, which may regulate dimerization of the receptors.

The membrane-bound ephrin ligands present in a clustered state to the Eph receptors. The extent of clustering may determine the level of activation of the Eph receptor. Importantly, the ephrins also have signaling capacity, and the class B ligands become tyrosine phosphorylated on binding their receptors. Thus, both EphB receptors and ephrin-B ligands are involved in bidirectional signaling.

Eph/Ephrin Signal Transduction

A large number of adaptor proteins, namely, SLAP, Grb2, GrblO Crk, and Nck, together with cytoplasmic signaling proteins such as RasGAP, Src, Abl, LMW-PTP, PLCg, and PI-3K, have been shown to interact with Eph receptors and their ligands in studies on patterning in the nervous system. These studies have established Eph/ephrin signaling in controlling neural cell morphology and architecture, attachment, and motility. In contrast, very little is known about Eph/ephrin signaling pathways in the endothelium and microvasculature. However, the adaptor protein Crk has been strongly implicated in ephrinBl-induced membrane ruffling and focal complex assembly in endothelial cells.

EphrinBl induces phosphorylation of EphBl in human endothelial cells and activates both Racl, resulting in membrane spreading, and Rapl, which mediates stabilization of focal complexes. These events depend on the adaptor function of Crk, which has been shown to associate with Ephs following their activation in other cell types. Ephrin-Bl transduces signals to modulate integrin-mediated cell attachment and migration in endothelial cells and promotes angio-genesis in vivo, although the signaling pathway has yet to be clearly defined. EphB2 and EphB4 have been shown to recruit pl20RasGap on activation and suppress VEGFR-and Tie2-mediated endothelial migration, but again further work will be required to establish the precise signaling cascades involved.

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