Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion

Abstract

Eph receptor tyrosine kinases and their corresponding surface-bound ligands, the ephrins, provide cues to the migration of cells and growth cones during embryonic development. Here we show that ephrin-A5, which is attached to the outer leaflet of the plasma membrane by a glycosyl-phosphatidylinositol-anchor, induces compartmentalized signaling within a caveolae-like membrane microdomain when bound to the extracellular domain of its cognate Eph receptor. The physiological response induced by this signaling event is concomitant with a change in the cellular architecture and adhesion of the ephrin-A5-expressing cells and requires the activity of the Fyn protein tyrosine kinase. This study stresses the relevance of bidirectional signaling involving the ephrins and Eph receptors during brain development.

The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization

“…Whereas complementary expression of ephrins and Eph receptors results in spatial segregation of receptor-bearing cells from ligand-bearing cells Xu et al, 1999), the functional consequences of coexpression of ephrins and Eph receptors are unknown. Because overlapping expression patterns allow for extensive interactions, binding of ephrin-A1 to EphA2 in tumor tissue could lead to activation of signaling pathways downstream of EphA2 and possibly ephrin-A1 (Kalo and Pasquale, 1999;van der Geer et al, 1994;Dodelet and Pasquale, 2000;Davy et al, 1999). Consistent with this hypothesis, we found that EphA2 is phosphorylated on tyrosine in the tumor xenografts.…”

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

“…Glycosylphosphatidylinositol-anchored ephrinA5 can induce compartmentalized signaling within a membrane microdomain when bound to its cognate Eph receptor. This signaling seemed to require the activity of the Fyn protein tyrosine kinase (Davy et al, 1999). We showed that ephrinA5 colocalized with EGFR in certain regions on the plasma membrane.…”

“…Although ephrinA5 is a glycosylphosphatidylinositol-linked membrane protein, it is also able to elicit intracellular signaling transduction, such as activation of Src family kinases (Davy et al, 1999). We supposed that the ephrin reverse signaling also participated in the downregulation of EGFR, considering the presence of endogeneous EphA receptors for ephrinA5.…”

Truncated Soluble Nogo Receptor Binds Nogo-66 and Blocks Inhibition of Axon Growth by Myelin

“…It is possible that Nogo affects NgR multimerization in neurons that may possess additional components required for Nogo signaling. It is also possible that ligand binding modifies the localization of additional unidentified signaling components within the lipid raft, as is the case for ephrins (Davy et al, 1999). Because the components of the NgR intracellular signaling cascade have not been identified, the effect of Nogo on the recruitment of signaling components to lipid rafts remains an open question.…”