ReviewEphs and ephrins in cancer: Ephrin-A1 signalling
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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2020, iScienceCitation Excerpt :Consistent with these observations, several studies have demonstrated that EPHA2 promotes cell migration and tumor malignancy in a ligand-independent manner. This signaling is characterized by high levels of S897 phosphorylation and low levels of Y772 and Y588 phosphorylation of EPHA2 (Miao et al., 2009; Beauchamp and Debinski, 2012; Brantley-Sieders, 2012; Zhou and Sakurai, 2017). In addition to ligand-independent activation, RTK heterodimerization and examples of alternative ligands binding to atypical receptors are well documented and is recognized as a means to amplify signal or induce functional diversity (Maruyama, 2014; Lemmon and Schlessinger, 2010).
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2018, Pathology Research and PracticeCitation Excerpt :A detailed mechanism of the entire process is described below: Upregulation of factors viz. FGF [32], VEGF [33], ephrin A1 [34] has been reported to facilitate angiogenesis leading to tumor metastasis. In another study, Song et al (2013) suggested that ephrin A1 is upregulated in response to HIF-1α, a hypoxia-inducible transcription factor, leading to upregulated expression of eNOS, stimulating neovascularisation in squamous cell carcinoma cells (SCC-9) [35] (Fig. 7A).