Harnessing the Power of Eph/Ephrin Biosemiotics for Theranostic Applications
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pharmaceuticals Review Harnessing the Power of Eph/ephrin Biosemiotics for Theranostic Applications Robert M. Hughes 1 and Jitka A.I. Virag 2,* 1 Department of Chemistry, East Carolina University, Science and Technology Building, SZ564, East 5th St, Greenville, NC 27858, USA; [email protected] 2 Department of Physiology, Brody School of Medicine, East Carolina University, Warren Life Sciences Building, LSB239, 600 Moye Blvd, Greenville, NC 27834, USA * Correspondence: [email protected] Received: 11 April 2020; Accepted: 27 May 2020; Published: 1 June 2020 Abstract: Comprehensive basic biological knowledge of the Eph/ephrin system in the physiologic setting is needed to facilitate an understanding of its role and the effects of pathological processes on its activity, thereby paving the way for development of prospective therapeutic targets. To this end, this review briefly addresses what is currently known and being investigated in order to highlight the gaps and possible avenues for further investigation to capitalize on their diverse potential. Keywords: Eph/ephrin; receptor tyrosine kinase; therapeutic target; smart drug; nanoparticles; liposomes; exosomes 1. Introduction Detection, transduction and appropriate response behavior of neighboring cells are essential components of optimal communication and the coordinated and integrated function necessary for survival. In a complex system, this is determined by the summative and timely intracellular processing of a myriad of intersecting signals from various distances and directions. The Eph receptors and ephrin ligands are the largest tyrosine kinase (RTK) superfamily, comprised of 22 known members, subdivided into A- and B-subclasses, and are heterogeneously expressed in almost every tissue [1]. These membrane-anchored proteins exhibit unique cell-to-cell communication via bidirectional signaling, which modulates cytoskeletal dynamics and thus cell–cell recognition and motility, making them integral mediators in developmental processes and the maintenance of homeostasis [2,3]. Given the importance of these biomolecules, it stands to reason that derangements in expression and signaling sequelae would contribute to and/or cause disease [4–10]. The disparate influences of aging, ethnicity, and gender on expression and signaling variations, however, which may exacerbate pre-existing imbalances, remain largely unexplored. Their complicated expression profiles, often with multiple ligands and/or receptors on one cell adjacent to or near other(s) with a different expression profile, compounded by their various affinities for receptor binding, oligomerization, cis- and trans-activation or inhibition, all contribute to the complicated delineation of their roles in normal physiology and disease progression, as well as development of customized, targeted therapeutics [11–17]. 2. Eph/ephrin is a Ubiquitous Therapeutic Target The Eph receptors (Eph = erythropoietin-producing hepatocellular) and their congeneric ligands, the ephrins (contraction of “Eph receptor interacting proteins” and after the Greek word “ephoros” meaning overseer or controller), are the largest family of receptor tyrosine kinases, comprised of 14 receptors and 8 ligands. Since their discovery and cloning by Hirai et al., published in Science in 1987 [18], more than 5000 articles have reported on the structure of these proteins, cellular Pharmaceuticals 2020, 13, 112; doi:10.3390/ph13060112 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2020, 13, x FOR PEER REVIEW 2 of 18 comprised of 14 receptors and 8 ligands. Since their discovery and cloning by Hirai et al., published inPharmaceuticals Science in2020 1987, 13 ,[18], 112 more than 5000 articles have reported on the structure of these proteins,2 of 17 cellular and tissue expression profiles, downstream signaling mechanisms, and their contribution to theand differentiation, tissue expression proliferation profiles, downstreamand migration signaling of various mechanisms, cell types. Ligands and their A1–A5 contribution and B1–B3 to are the typicallydifferentiation, membrane-anchored, proliferation and and migration cell-to-cell of contac varioust is cellusually types. but Ligands not always A1–A5 required, and B1–B3 resulting are intypically binding membrane-anchored, with varying affinity and and cell-to-cell promiscuity contact to is the usually receptors but not A1–A8, always A10, required, B1–B4, resulting and B6. in Subsequentbinding with dimerization, varying affinity tetramerization and promiscuity and/or to the clustering receptors of A1–A8, ligands A10, and B1–B4, receptors and (Figure B6. Subsequent 1A) can causedimerization, activation tetramerization or silencing andof bi-directional/or clustering ofsignaling ligands and receptorsconsequent (Figure activation1A) can (or cause inhibition) activation of intracellularor silencing of cascades bi-directional in each signaling cell [19–24]. and consequent Ojosnegros activation et al. (or (2017) inhibition) recently of intracellular adapted enhanced cascades fluorescencein each cell [19 fluctuation–24]. Ojosnegros imaging et al.analysis (2017) recentlyto resolve adapted the spatial enhanced relationships fluorescence of polymerization fluctuation imaging and formationanalysis to of resolve larger aggregates, the spatial relationshipsgenerating a model of polymerization of polymerization-condensation and formation of larger dynamics aggregates, which suggestsgenerating that a modelthese associations of polymerization-condensation result not only in amplification dynamics which of the suggests signal, but that also these in associationstermination [25].result To not complicate only in amplification matters, domain of the signal, mutation but alsoanalyses in termination have revealed [25]. Tothat complicate the nature matters, of the domaincontact interfacesmutation analysesin the ligand-binding have revealed domains that the nature confer of binding the contact specificity, interfaces but in it the is ligand-bindingthe domains contained domains withinconfer bindingectodomains specificity, (e.g., but SAM—sterile it is the domains alpha contained motif) that within are ectodomains indispensable (e.g., for SAM—sterile localization alpha and subsequentmotif) that areforward indispensable intracellular for localization signaling and[26–28 subsequent]. Lastly, forwardthe importance intracellular of the signaling lipid [bilayer26–28]. compositionLastly, the importance [29], as well of the as lipidits interface bilayer composition as a regulator [29 ],of as their well orientation as its interface and as configuration a regulator of with their respectorientation to the and membrane, configuration as demonstrated with respect to by the char membrane,ge-swapping as demonstrated simulations [30], by charge-swapping illustrates their effectualsimulations plasticity. [30], illustrates their effectual plasticity. Figure 1. ((AA)) ManyMany configurations configurations and and post-translational post-translational modifications modifications of Ephof Eph/ephrin/ephrin RTKs RTKs have have been beenobserved observed (Me—methylation, (Me—methylation, P—phosphorylation, P—phosphorylation, Ac—acetylation). Ac—acetylation). (B) Eph (B/ephrin) Eph/ephrin RTKs areRTKs widely are widelyexpressed expressed in various in cellvarious types cell in mosttypes healthy in most tissues healthy with tissues the following with the exceptions:following exceptions: EphA8 is detected EphA8 isonly detected in spleen, only brain in spleen, and testes, brainEphA10 and testes, is in EphA10 testes only, is in and testes ephrinA2 only, and is absent ephrinA2 in lung, is absent spleen, in testes,lung, spleen,and bone testes, marrow and (Createdbone marrow with (Created BioRender.com). with BioRender.com). The multifaceted multifaceted and and ubiquitous ubiquitous ex expressionpression of Eph/ephrin of Eph/ephrin RTKs RTKs in nearly in nearly all cells all of cells the ofbody, the althoughbody, although most extensively most extensively studied studiedin cancer in and cancer development, and development, implicates implicatesthem in the them majority in the of vitalmajority physiologic of vital processes physiologic (Figure processes 1B) [3]. (Figure The kn1B)owledge [ 3]. Thewe have knowledge acquired we from have these acquired studies from has generatedthese studies valuable has generated information valuable about the information role of Eph/ephrin about the RTKs role ofin Ephcellular/ephrin communication RTKs in cellular and behavior,communication providing and a behavior, wealth of providingtherapeutic a targeting wealth of opportunities therapeutic targetingthat may opportunitiesbe exploited for that a range may ofbe pathologies, exploited for including a range but of pathologies,not limited to including atherosclerosis but not [5,31,32], limited neurodegenerative/cognitive to atherosclerosis [5,31,32], andneurodegenerative endocrine disorders/cognitive [33–38], and endocrinegastrointestinal disorders and [33genito-urinary–38], gastrointestinal maladies and [39–41], genito-urinary immune maladies [39–41], immune disorders [4,5,9], musculoskeletal growth and metabolism diseases [42–45], Pharmaceuticals 2020, 13, x FOR PEER REVIEW 3 of 18 Pharmaceuticals 2020, 13, 112 3 of 17 disorders [4,5,9], musculoskeletal growth and metabolism diseases [42–45], ischemic tissue injury [46–56] and malignancies [7,57,58], reproductive/fertility illnesses [59–62] and organ fibrosis [10,63]. ischemic tissue injury [46–56] and malignancies [7,57,58], reproductive/fertility illnesses