Pathway Map Details
Cell adhesion_Ephrins signaling
Object list (links open in MetaCore):
p120GAP, RHO6, PAK1, Ephexin, Ephrin-A5, Grb4, PI3K cat class IB, CDC42, NCK1, Ephrin-A receptors, Intersectin, VAV-2, RAP-1A, Ephrin-A receptor 8, Paxillin, ADAM10, Ephrin-A, Ephrin-B receptor 1, TAK1, c-Src, Fyn, Tiam 1, G-protein alpha-i, HGK, H-Ras, glycosyl- phosphatidyl- inositol, GRB2, Fyn, GRB7, Ephrin-B, PtdIns(3,4,5)P3, PtdIns(4,5)P2, Ephrin-A2, Ephrin-B receptors, c-Raf-1, 188.8.131.52, FAK1, RGS3, Ephrin-A receptor 2, FAK1, c-Src, RhoA, Rac1, GRB10, SLAP, Kalirin, FAP-1, JNK1
The Ephrin receptor tyrosine kinases and their Ephrin ligands play a pivotal role during axon guidance, synaptogenesis, neuronal circuitry formation, angiogenesis and proliferation of neuronalstem cells . Ephrin receptors and Ephrin ligands transduce intracellular responses only upon binding and clustering in the membrane .
Ephrin-A receptors (Ephrin-A receptors 1-8) bind glycosylphosphatidyl-anchored Ephrin-A ligands (Ephrin-A1-5), whereas Ephrin-B receptors (Ephrin-B receptors 1-6) bind transmembrane Ephrin-B ligands (Ephrin-B1-3) .
In the absence of Ephrin-A stimulation, Ephrin-A receptors alternatively engage Ephexin at the plasma membrane. This interaction induces Ephexin phosphorylation by c-Src tyrosine kinase  and this phosphorylation enhances Ephexin activity toward the GTPase RhoA and not Rac1 or CDC42 .
RhoA -dependent signaling in both cases leads to the growth cone retraction and collapse.
The growth cone collapse may be due to Rac1 -dependent endocytosis events. Following Ephrin-A activation, VAV-2 induces activation of Rac1 which leads to actin cytoskeleton reorganization and endocytosis .
Ephrin-A receptors also signal through the Rac1 exchange factor Tiam 1 to promote neurite outgrowth .
Ephrin-A receptor 8 localizes p110gamma isoform of phosphatidylinositol 3-kinase ( PI3K cat class IB (p110-gamma) ) to the plasma membrane, thereby allowing access to lipid substrates that facilitate integrin-mediated cell adhesion .
Guanine exchange factors Kalirin and Intersectin are downstream effectors of Ephrin-B receptors. Kalirin and Intersectin promote dendritic spine morphogenesis by modulating Rac1 and CDC42 activity, respectively . Intersectin binds to Ephrin-B receptors independently of activation by Ephrins, while Kalirin appear to require Ephrin stimulation. Kalirin is also phosphorylated on tyrosine residues following Ephrin-B receptors activation .
The majority of Ephrin receptors negatively regulate the Ras/ MAP-kinase pathways in most cell types . For instance, Ephrin-B receptor 2 via GTPase activated protein (GAP), p120GAP, down-regulates H-Ras activity and MAP kinase phosphorylation and induces neurite retraction in the some neuronal cell lines  However the phosphorylation of p120GAP by c-Src inhibites its GAP activity . Ephrin-A1 stimulation leads to Ras-related protein Rap-1A activation  and inhibits MAPK signaling cascade by decreasing c-Raf-1 kinase activation . Alternatively c-Raf-1 can also be phosphorylated and activated by PAK1 . Recruitment of the adaptor proteins GRB2 and GRB10 to the activated Ephrin-B receptor 1 also promotes MAP-kinase activation , .
Ephrin-B receptor 1 and Ephrin-B receptor 2 bind adaptor protein NCK1, thereby increasing the activity of specifically Nck-interacting kinase HGK . HGK -induced JNK (stress-activated protein kinases) activation leads to the phosphorylation of Paxillin by JNK, which is essential for maintaining the dynamic cytoskeletal remodeling required for rapid cell migration .
Ephrin receptors also maintain feedback mechanisms that reverse signaling through their Ephrin ligands .
Src family kinases are responsible for Ephrin-B phosphorylation upon Ephrin receptor engagement . The adaptor protein GRB4 links Ephrin-B to a vast signaling network that modifies cell morphology through reorganization of the actin cytoskeleton. Phosphorylated Ephrin-B recruits the phosphotyrosine phosphatase FAP-1, that dephosphorylates the cytoplasmic domain of Ephrin-B .
The GTPase-activating protein RGS3, can also transduce Ephrin-B signaling by catalyzing the hydrolysis of GTP to GDP in the alpha-i-subunits of G-proteins ( G-protein alpha-i family ). This signaling mechanism has broad implications for cell migratory behavior in different systems .
Ephrin-A ligands can also induce signals that modify cell behavior. Clustering of Ephrin-A molecules with Ephrin-A receptors recruits the Src family kinase Fyn to lipid rafts. This is accompanied by activation of MAP kinases and leading to an increase in cellular adhesion , .
Inhibition of Ephrin-A signaling may be modulated at the cell surface by induction of ligand-receptor dissociation by the metalloprotease ADAM10. Upon binding of Ephrin-A receptors, ADAM10 cleaves Ephrin-A2 ligands from the cell surface , serving two functions: 1) Ephrin-A cleavage allows Ephrin-A-receptor -bearing structures such as growth cones to revert from cellular adhesion to repulsion, and 2) ligand cleavage leads to direct inhibition of receptor activation .
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