Hindawi BioMed Research International Volume 2018, Article ID 7390104, 23 pages https://doi.org/10.1155/2018/7390104 Review Article Differential Expression Patterns of Eph Receptors and Ephrin Ligands in Human Cancers Chung-Ting Jimmy Kou and Raj P. Kandpal Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA Correspondence should be addressed to Raj P. Kandpal; [email protected] Received 29 September 2017; Revised 11 January 2018; Accepted 22 January 2018; Published 28 February 2018 AcademicEditor:PasqualeDeBonis Copyright © 2018 Chung-Ting Jimmy Kou and Raj P. Kandpal. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Eph receptors constitute the largest family of receptor tyrosine kinases, which are activated by ephrin ligands that either are anchored to the membrane or contain a transmembrane domain. Tese molecules play important roles in the development of multicellular organisms, and the physiological functions of these receptor-ligand pairs have been extensively documented in axon guidance, neuronal development, vascular patterning, and infammation during tissue injury. Te recognition that aberrant regulation and expression of these molecules lead to alterations in proliferative, migratory, and invasive potential of a variety of human cancers has made them potential targets for cancer therapeutics. We present here the involvement of Eph receptors and ephrin ligands in lung carcinoma, breast carcinoma, prostate carcinoma, colorectal carcinoma, glioblastoma, and medulloblastoma. Te aberrations in their abundances are described in the context of multiple signaling pathways, and diferential expression is suggested as the mechanism underlying tumorigenesis. 1. Introduction of human cancers. We have focused here on Eph/ephrin molecules and their roles in tumorigenesis. Te discovery of oncogenes and tumor suppressors in 1970s and subsequent advances in 1980s illuminated the mecha- 2. Structure of Eph Receptors and nisms responsible for regulating the growth and prolifera- Ephrin Ligands tion of normal cells. Te activation of protooncogenes and inactivation of tumor suppressors are frequently observed in Eph receptors are important for development and tissue cancer cells. In most cases, tumor cells display alterations organization in multicellular organisms. Tese transmem- in morphology, cell-cell interactions, membrane properties, brane (TM) proteins are activated by binding to ephrin cytoskeletal structure, protein secretion, and gene expression. ligands. Fourteen Eph receptors encoded in the human Furthermore, transformed cells also exhibit loss of contact genome are divided into A and B classes. EphA receptors inhibition, self-sufciency of growth signals, and escape from consist of nine members (EphA1–EphA8 and EphA10), which replicative senescence [1–4]. areactivatedbyfvediferentephrin-Aligands.FiveEphB Te growth and consequent metastasis of tumor cells receptors (EphB1–EphB4 and EphB6) bind to three ephrin- are largely dependent on neovascularization [5], which B ligands [7]. Although interactions of Eph receptors with is regulated by many diferent cellular signals including theircognateclassofephrinligandsarewelldocumented, axon guidance molecules. Axon guiding signal molecules interclass binding between Eph receptors and ephrin ligands consist of Eph/ephrin, Semaphorins/plexins, VEGF/VEGFR, has also been reported. chemokines/chemokine receptors, netrins/DCC, Slit/Robo, Te native structure of Eph receptors displays an ephrin- and Notch/Delta [6]. In fact, altered abundance and regu- binding domain, a cysteine-rich region, two fbronectin lation of these proteins have been associated with a variety type III repeats, a transmembrane segment with conserved 2 BioMed Research International Ephrin binding domain Cysteine-rich region Fibronectin type III repeats Extracellular P Juxtamembrane region Intracellular P Kinase domain SAM domain P PDZ domain Eph receptor Figure 1: Domains in Eph Receptors. Te cytoplasmic and extracellular portions of the receptor are separated by the membrane bilayer. Te extracellular region of Eph receptors contains a ligand binding domain, a cysteine-rich domain, and two fbronectin type III repeats. Te intracellular region is composed of a tyrosine domain, a sterile � motif (SAM), and a PDZ domain. Te domains have been drawn in diferent shapes and colors, and individual domains are labeled with their designations. Phosphorylated residues are indicated. Ephrin A Ephrin B Eph binding domain Eph binding domain GPI anchor Transmembrane domain Extracellular Intracellular P Cytoplasmic domain PDZ domain Figure 2: Structure of Ephrin Ligands. Te GPI anchor and transmembrane domains of ephrin-A and ephrin-B are shown. Both classes have Eph binding domain on the extracellular side. Ephrin-B contains a cytoplasmic domain and a PDZ domain. tyrosine residues, a kinase domain, a sterile � motif (SAM) binding domain of the ephrin ligand is attached to the plasma protein-protein interaction domain, and a C-terminal PDZ- membrane by a linker segment of variable length [17]. Te two binding motif [17–19]. Te arrangement of these domains classes of ligands are distinguished by the presence of GPI and motifs in Eph receptors is schematically represented anchor in ephrin-A ligands and a transmembrane segment in Figure 1. Tese domains and regions contribute to the in ephrin-B ligands [21]. Te structural features of the two 3D topology of the protein and facilitate its interaction classes of ephrins are illustrated in Figure 2. with other proteins within the cellular signaling network. Phosphorylated amino acid residues in the activated Eph 3. Physiological Roles of Eph Receptors and receptors mediate these interactions. However, EphA10 and Ephrin Ligands EphB6 lack kinase activity due to altered sequence of the conserved regions within the kinase domain [20]. Te spatial organizations of Eph receptors and ephrin ligands Eph receptors are activated by binding of ephrin ligands require the presence of these molecules on the surface of two to the ephrin-binding domain in the receptor. Te Eph interacting cells of the same or diferent types. Tus, physical BioMed Research International 3 contact is necessary for initiating forward and/or reverse remodeling [102, 133]. Ephrin-B2 is also necessary for blood signaling in diferent cell types. Such contact-mediated vessel network stabilization [134, 135]. physiological functions of these receptor-ligand pairs have been extensively documented for axon guidance, neuronal 3.4. Tissue Injury. Te healing of injured or infamed ves- development, vascular patterning, and wound healing as sels occurs by platelet plug formation and coagulation of described below. extravasated blood. Tis process involves signaling pathways that facilitate the recruitment of infammatory cells and 3.1. Axon Guidance. Axons in the nervous system extend proliferation of fbroblasts and epithelial cells. Eph/ephrin over long distances to reach their targets, and this process proteinspartakeintissuehealingasregulatorsofangio- is facilitated by Eph receptors and ephrins. Attraction or genesis [19] and cell migration [136]. Eph/ephrin regula- repulsion of growth cones, which are large actin-supported tion has also been observed in renal ischemic injury [137]. extensions of a growing neurite, modulate axonal spread Upregulation of Eph/ephrin expression in hypoxic mouse [112]. Interactions of ephrin-As with TrkB and p75 neu- skin fap models supports the hypothesis of Eph/ephrin rotrophinreceptorleadtoaxonpathfndingandelongation involvement in ischemic tissue injury repair [138]. Similarly, via reverse signaling [113]. Ephrin-Bs recruit cytoskeleton remodeling events following optic nerve injury in EphB3 null regulators for axon guidance, dendrite morphogenesis, and rodents resulted in decreased axon sprouting due to impaired postsynapse maturation [113]. While several other important interaction between macrophages and retinal ganglion cell molecules such as Zic2, neuropilin-1 (NRP1), and NrCAM axons [139]. Lastly, immunochemistry data showed EphB3 are involved in guiding retinal ganglion axons, induction of overexpression in invading fbroblasts and ephrin-B2 expres- EphB receptors by Zic2 transcription factor substantiate the sion in astrocytes during spinal cord injury [140]. EphA4 has central role of Eph/ephrin signaling in axon guidance during been implicated in the formation of astrocytic gliosis and scar neurogenesis [114–119]. formation following spinal injury in rodents and nonhuman primates [141, 142]. Tese observations indicate Eph/ephrin 3.2. Neural Development. Neural progenitor cell prolifera- involvement in the events that follow tissue injury. tion, neuroblast migration, neuron survival, and neuronal plasticity also depend on Eph-ephrin interactions. Te acti- 4. Eph/Ephrin Signaling System vation of EphB1, EphB2, EphB3, and EphA4 by ephrin ligands leads to migration of neuroblasts in the subventricular Eph receptors constitute the largest family of receptor tyro- zone of the lateral ventricles in the adult mammalian brain sine kinases (RTK). Several features of the Eph-ephrin family [120]. Ephrin-A5 is required for the survival of newborn distinguish it from other RTK families. RTK are activated neurons in adult mice hippocampus, proliferation of cells by binding to soluble ligands, but Eph