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

Table 2

Altered expression of Eph receptors and ephrin ligands in breast cancer.

Eph receptor/ephrin ligand	Preferred molecular interaction	↑/↓ relative to normal tissue	Mechanism	References
EphA2	Ephrin-A1	↑	(i) Ligand-dependent ephrin-A1 activation suppresses migration & ligand-independent activation promotes migration; (ii) Herceptin exposure results in Src kinase phosphorylation of EphA2→ activation of PI3K/Alt & MAPK; (iii) Ligand-dependent phosphorylation by Erbb2→ amplification of oncogenic Ras/MAPK and RhoA signaling; (iv) Anks1 facilitates COPII vesicle loading of ErB2/EphA2 from ER to membrane surface	[12, 13, 34, 35]
EphA4		↑	(i) Higher levels of mRNA EPhA4 → worse prognosis	[36]
EphA7		↑	(i) Higher mRNA of EphA7→ worse prognosis; (ii) EphA7–EphA10 heterodimer formation & EphA7–EphA10 nucleus signaling detected in aggressive breast cancer; (iii) EphA7–EphA10 cellular signaling detected in normal mammary epithelial cells and EphB6 expressing breast tumors	[36, 37]
EphA10		↑	(i) Higher mRNA of EphA10 → worse prognosis; (ii) EphA7–EphA10 heterodimer formation and EphA7–EphA10 nucleus signaling detected in aggressive breast cancer; (iii) EphA7–EphA10 cellular signaling detected in normal mammary epithelial cells and EphB6 expressing breast tumors	[37, 38]
EphB2		↑	(i) Localization of EphB2 influence prognostic; (1) Worse prognostic in cytoplasmic EphB2; (2) Better prognostic in membranous EphB2; (ii) EphB2/EphB6 heterodimer formation → potential localization of EphB2 based on heterodimer formation	[39, 40]
EphB4	Ephrin-B2	↑ & ↓; (paradoxical)	(i) Ephrin-B2 binding→ activation of Abl-Crk→ downregulation of MMP-2; (ii) Mutant Ephrin-B2 → disrupted E-cadherin expression; (1) E-cadherin shedding as a result of ADAM10; (2) EphB regulate ADAM10 activation; (iii) EphB4/Ephrin-B2 signaling in MCF7 null PP2A→ activation of oncogenic ERK pathway; (iv) ErbB induced expression of EphB4→ inhibition of JAK-STAT & PI3k-AKT pathway	[41–45]
EphB6	Ephrin-B1; Ephrin-B2	↓	(i) EphB6 expression regulated by methylation; (1) Inverse relationship between EphB6 and cadherin 17 levels; (2) Cadherin 17 activates oncogenic WNT pathway; (ii) Kinase null→ phosphorylation via heterodimer formation; (iii) EphB6/EphB2 heterodimer; (iv) Ephrin-B1 binding→ EphB6/EphB1; (v) Ephrin-B2 binding→ EphB6/EphB4; (1) Heterodimer interacts with c-CBL and phosphorylation of Abl kinase → adhesion promotion; (vi) EphB6-EphA2 cross-talking → stabilization of oncogenic ligand-independent EphA2 activation; (vii) MDA-MB-231 cells infected with EpB6 revealed decreased transcripts of SMARCC1, eIFC4, eIF4EB2, FKBP1a, FKZBPD5, TRIB1, TRIB3, BMPR1a, and BMPR2	[15, 39, 46–49]
Ephrin-B1	EphB6 Receptor		(i) Binding of ephrin-B1 to EphB6 leads to the formation of heterodimers with EphB1 followed by the phosphorylation of kinase null EphB6; (ii) In vivo in COS-7 revealed Cross-talk of ephrin-B1 activates kinase null EphB6 receptor	[46, 47, 50]
Ephrin-B2	EphB4 Receptor		(i) Interaction of ephrin-B2 results in heterodimer formation between EphB4 and EphB6 with trans phosphorylation of EpB6 and activation of Cbl-Abl pathway leading to proadhesive cell properties in MCF7, MDA-MB-231, and MDA-MB-435; (ii) Protein phosphatase PP involved in ERK pathway activation in ephrin-B2 treated MCF-7 cells; (iii) Mutant ephrin-B2 transgenic mice showed aberrant expression of E-cadherin	[42–44, 47, 51, 52]