Differential Expression Patterns of Eph Receptors and Ephrin Ligands in Human Cancers

Table 3

Altered expression of Eph receptors and ephrin ligands in gliomas.

Eph/ephrin ligand	Preferred ligand	↑/↓ relative to normal	Mechanism	Reference
EphA2	Ephrin-A1	↑	(i) Overexpression of EphA2 → decreased ERK signaling (ERK crucial in neuronal differentiation in embryonic stem cells); (ii) Ephrin-A1 binding results in ↓EphA2 expression; (1) Soluble ephrin-A1 can bind to EphA2 and downregulate EphA2 expression in U251 GMB cells; (2) Ephrin-A1 has shown to downregulate focal adhesion kinase in GBM cells resulting in ↓ migration, adhesion, and proliferation; (iii) Cross-talking of EphA2 and Akt results in phosphorylation of EphA2; (1) EphA2 expression downregulates Sox2; (iv) Sox2 crucial protein in stem property maintenance	[53–59]
EphA3	Ephrin-A5	↑	(i) Ephrin-A5 binding results in ↑c-Cbl of EGFR receptor → increased degradation of EGFR receptor; (ii) GBM cells with overexpression of EphA2, EphA3, and EphB2 killed when exposed to chimeric eA5-PE-C; (iii) Expression of EphA3 results in limiting ERK/MAPK activation; (1) MAPK signaling drives differentiation of neuronal progenitors	[60–63]
EphA4		↑	(i) Heterodimer complex EphA4-FGFR1 complex → potentiate FGFR mediate downstream signaling to increase proliferation and migration in U251 GBM cells	[64]
EphA5		↑	(i) EphA5 overexpressed in GMB; (1) Ligand stimulation with ephrin-A1 did not result in decreased cell proliferation or migration; (ii) GBM disease progression correlated with decrease plasma EphA5	[65, 66]
EphA7		↑	(i) Predicator of poor clinical outcome in primary and recurrent GBM patients	[67]
EphA8	Ephrin-A5	↑	(i) Expression of EphA8 → sustained MAPK activity resulting in induced neurite outgrowth in NG108-15 cells; (ii) Ephrin-A5 ligand activated EphA8 → no modulation on MAPK activity	[68]
EphB2		↑	(i) Increased expression EpHb2 in human GBM; (1) Positive correlation of EphB2 expression and GBM grade; (ii) miR-204 posttranscriptional regulator of EphB2; (1) miR-204 reduced in glioma cells due to hypermethylation of host gene TRPM3; (2) miR-204 targets SOX4 and EphB2; (iii) EphB2 has pro-migratory and antiproliferation properties mediated; (1) FAK mediates EphB2 migration; (2) FAK inhibitors reduced migration in xenograft of EphB2 overexpressing cells; (iv) EphB2 activate R-Ras (GTPase)→ decreased extracellular adhesion	[69–72]
EphB4	Ephrin-B2	↑	(i) Higher expression of EphB4 correlated to further progression & worse prognosis of GBM patient	[73]
Ephrin-B2	EphB4	↑	(i) Higher ephrin-B2 associated with worse prognosis; (ii) Enhanced migration & invasion with higher expression of ephrin-B2	[73, 74]
Ephrin-B3	EphB2	↑	(i) Possible autocrine or paracrine loop mediated by EphB2 and ephrin-B3; (1) Endogenous ephrin-B3 phosphorylated by EphB2/Fc and exogenous ephrin-B3 phosphorylated; (2) Reverse EphB2 signaling dependent on ephrin-B2 in U251 and SnB19 cells; (ii) Ephrin-B3 mediates cell migration and invasion through Rac-1 (GTPase); (iii) Rac-1 vital to cytoskeletal organization and plasticity	[75, 76]