Review
Ephs and ephrins in cancer: Ephrin-A1 signalling

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Abstract

Ephrin-A1 and its primary receptor, EphA2, are involved in numerous physiological processes and have been intensely studied for their roles in malignancy. Ephrin–Eph signalling is complex on its own and is also cell-type dependent, making elucidation of the exact role of ephrin-A1 in neoplasia challenging. Multiple oncogenic signalling pathways, such as MAP/ERK and PI3K are affected by ephrin-A1, and in some cases evidence suggests the promotion of a specific pathway in one cell or cancer type and inhibition of the same pathway in another type of cell or cancer. Ephrin-A1 also plays an integral role in angiogenesis and tumor neovascularization. Until recently, studies investigating ephrins focused on the ligands as GPI-anchored proteins that required membrane anchoring or artificial clustering for Eph receptor activation. However, recent studies have demonstrated a functional role for soluble, monomeric ephrin-A1. This review will focus on various forms of ephrin-A1-specific signalling in human malignancy.

Introduction

Since their discovery, ephrins and Ephs have been extensively studied for their role in normal physiology and development. Initial indications of ephrin-A1 upregulation during melanoma progression [1] and eph overexpression in multiple human malignancies pointed toward the Eph/ephrin family as important players in tumorigenesis [2]. Ephrin-A1 was discovered in 1990 as a novel TNF-inducible protein in human umbilical vein endothelial cells (HUVECs) [3], but it was not until 1994 that it was identified as a ligand for the EphA2 receptor, which was at that time considered an orphan receptor tyrosine kinase (RTK) since its discovery in 1987 [4], [5]. Several reviews have been published specifically focusing on EphA2 and ephrin-A1 in carcinogenesis as well as outlining ways in which the ephrin-A1/EphA2 system can be utilized for cancer therapies [6], [7], [8], [9]. In this review, we will describe more in detail the role of ephrin-A1 in signalling events potentially leading to the initiation and progression, or inhibition of human malignancy.

Section snippets

Ephrin-A1 structure–function relationship

The ephrin family consists of eight members, divided into A and B subclasses based on their mode of cell membrane attachment. Ephrin-A1–A5 are linked to the membrane via a glycosylphosphatidylinositol (GPI) moiety, while ephrin-B1–B3 are anchored by a transmembrane domain and contain a cytoplasmic tail [10]. Due to their membrane localization, ephrins are able to engage in both forward and reverse signalling [11]. While more is known about reverse signalling through the ephrin-B cytoplasmic

Ephrin-A1 expression in malignancy

In addition to playing an important role in normal cellular processes, ephrin ligands and Eph receptors have come under intense scrutiny for their roles in human malignancy. Paradoxically, ephrin-A1 and EphA2 have been shown to influence both tumor initiation and progression [8], [9], [18]. Ephrin-A1 and EphA2 are upregulated during melanoma progression [1], and high expression of the receptor and ligand has been correlated with poor patient survival in ovarian cancer [19]. Similar increased

Evidence for functional, soluble ephrin-A1

Previous studies investigating the function of ephrin-A1 and EphA2 have focused on the ligand as a membrane-bound, GPI-anchored protein capable of mediating juxtacrine signalling and requiring membrane attachment or clustering/oligomerization [34]. This requirement was thought to be due to the necessity of Eph receptors themselves to undergo clustering in order to be activated [35]. This review underlines the importance of a functional form of ephrin-A1 that is released into the extracellular

Ephrin-A1-independent functions of EphA2

Multiple studies have documented low levels of EphA2 phosphorylation in malignant cells compared to normal cells despite its overexpression [7]. In addition to a deficiency in cell–cell contact, which is common in cancer cells, a lack of sufficient amounts of ephrin-A1 on tumor cells could result in the decrease in EphA2 phosphorylation [7], [24]. Evidence suggests that in cases with sufficient ligand and receptor expression, EphA2 is activated by ephrin-A1 and phosphorylated, but is quickly

Ephrin-A1 and cytoskeletal organization and cell migration

Ephrin-A1 and EphA2 play an important role in cell migration by influencing cell–cell and cell–extracellular matrix (ECM) interactions. EphA2 activation by ephrin-A1 decreases cell attachment to ECM and counteracts integrin signalling in multiple cells types leading to Rac-mediated upregulation of Rho activity [46], [47]. It has also been proposed that reactive oxygen species (ROS) play a role in this process whereby ephrin-A1 interaction with EphA2 leads to the downregulation of Rac1-dependent

Ephrin-A1 function in malignancy: role in angiogenesis and tumor neovasculature

Ephrin-A1 and EphA2 are not only expressed in multiple tumor types, but are also expressed and play an important role in normal angiogenesis and tumor neovascularization.

Conclusions

Overall, even though much research has been focused on ephrins and their receptors over the past couple of decades, their exact complex roles in malignancy have not been fully elucidated. What is apparent, however, is that their expression and the signalling pathways activated by that expression is cell-type and microenvironment dependent. In all tumor types ephrin-A1 and its primary receptor affect multiple oncogenic signalling pathways such as MAP/ERK, and PI3K. In addition, multiple

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