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Zika virus (ZIKV) infection is a serious public threat with cases reported in about 70 countries and territories. One of the most serious consequences of ZIKV infection is congenital microcephaly in babies. Congenital microcephaly has been suggested to result from infection of neural progenitor cells (NPCs) in the developing fetal brain. However, the molecular and cellular mechanisms underlying microcephaly development remains to be fully elucidated. In this study, we employed quantitative proteomics to determine protein expression profile that occur during viral replication in NPCs. Bioinformatics analysis of the protein expression changes resulted in the identification of a wide range of cell signaling pathways. Specifically, pathways involved in neurogenesis and embryonic development were markedly altered, along with those associated with cell cycle, apoptosis, lipid metabolism and oxidative stress. Notably, the differential regulation of Ephrin Receptor and PPAR signaling pathways, as revealed by quantitative proteomics and validated by qPCR array, underscores the need to explore these pathways in disease development. Collectively, these results indicate that ZIKV-induced pathogenesis involves complex virus-host reactions; the findings reported here could help shed light on the mechanisms underlying ZIKV-induced microcephaly and ZIKV replication in NPCs.

Introduction: Erythropoietin-producing human hepatocellular (Eph) receptors are among the largest family of tyrosine kinases that are divided into two classes: EphA and EphB receptors. Over the past two decades, their role in cancer has become more evident., Areas Covered: There is a need for new anticancer treatments and more insight in the emerging role of Eph receptors in cancer. Molecular mechanisms underlying the pro-tumorigenic effects of Eph receptors could be exploited for future therapeutic strategies. This review describes the variability in expression levels and different effects on oncogenic and tumor suppressive downstream signaling of Eph receptors in various cancer types, and the small molecules, antibodies and peptides that target these receptors., Expert Opinion: The complexity of Eph signaling is a challenge for the definition of clear targets for cancer treatment. Nevertheless, numerous drugs that target EphA2 and EphB4 are currently in clinical trials. However, some Eph targeted drugs also inhibit other tyrosine kinases, so it is unclear to what extent the targeting of Eph receptors contributes to their efficacy. Future research is warranted for an improved understanding of the full network in which Eph receptors function. This will be critical for the improvement of the anticancer effects of drugs that target the Eph receptors.

The orientation of the mitotic spindle is a crucial process during development and adult tissue homeostasis and multiple mechanisms have been shown to intrinsically regulate this process. However, much less is known about the extrinsic cues involved in modulating spindle orientation. We have recently uncovered a novel function of Eph intercellular signaling in regulating spindle alignment by ultimately ensuring the correct cortical distribution of central components within the intrinsic spindle orientation machinery. Here, we comment on these results, novel questions that they open and potential additional research to address in the future.

Eph:ephrin signaling plays an important role in embryonic development as well as tissue homeostasis in the adult. At the cellular level, this transduction pathway is best known for its role in the control of cell adhesion and repulsion, cell migration and morphogenesis. Yet, a number of publications have also implicated Eph:ephrin signaling in the control of adult and embryonic neurogenesis. As is the case for other biological processes, these studies have reported conflicting and sometimes opposite roles for Eph:ephrin signaling in neurogenesis. Herein, we review these studies and we discuss existing mathematical models of stem cell dynamics and neurogenesis that provide a coherent framework and may help reconcile conflicting results.

Proteases regulate a myriad of cell functions, both in normal and disease states. In addition to protein turnover, they regulate a range of signaling processes, including those mediated by Eph receptors and their ephrin ligands. A variety of proteases is reported to directly cleave Ephs and/or ephrins under different conditions, to promote receptor and/or ligand shedding, and regulate receptor/ligand internalisation and signaling. They also cleave other adhesion proteins in response to Eph-ephrin interactions, to indirectly facilitate Eph-mediated functions. Proteases thus contribute to Eph/ephrin mediated changes in cell-cell and cell-matrix interactions, in cell morphology and in cell migration and invasion, in a manner which appears to be tightly regulated by, and co-ordinated with, Eph signaling. This review summarizes the current literature describing the function and regulation of protease activities during Eph/ephrin-mediated cell signaling.

There is increasing evidence that in addition to having major roles in morphogenesis, in some tissues Eph receptor and ephrin signaling regulates the differentiation of cells. In one mode of deployment, cell contact dependent Eph-ephrin activation induces a distinct fate of cells at the interface of their expression domains, for example in early ascidian embryos and in the vertebrate hindbrain. In another mode, overlapping Eph receptor and ephrin expression underlies activation within a cell population, which promotes or inhibits cell differentiation in bone remodelling, neural progenitors and keratinocytes. Eph-ephrin activation also contributes to formation of the appropriate number of progenitor cells by increasing or decreasing cell proliferation. These multiple roles of Eph receptor and ephrin signaling may enable a coupling between morphogenesis and the differentiation and proliferation of cells.

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, and mediate many other cell-cell communication events. The Ephs and ephrins both localize to the plasma membrane and, upon cell-cell contact, form extensive signaling assemblies at the contact sites. Recent structural, biochemical and cell-biological studies revealed that these assemblies are generated not only via Eph-ephrin interactions, but also via homotypic interactions between neighboring receptor molecules. In addition, Eph-Eph interactions mediate receptor pre-clustering, which ensures fast and efficient activation once ligands come into contact range. Here we summarize the current knowledge about the homotypic Eph-Eph interactions and discuss how they could modulate the initiation of Eph/ephrin signaling.

Epithelial cells are tightly coupled together through specialized intercellular junctions, including adherens junctions, desmosomes, tight junctions, and gap junctions. A growing body of evidence suggests epithelial cells also directly exchange information at cell-cell contacts via the Eph family of receptor tyrosine kinases and their membrane-associated ephrin ligands. Ligand-dependent and -independent signaling via Eph receptors as well as reverse signaling through ephrins impact epithelial tissue homeostasis by organizing stem cell compartments and regulating cell proliferation, migration, adhesion, differentiation, and survival. This review focuses on breast, gut, and skin epithelia as representative examples for how Eph receptors and ephrins modulate diverse epithelial cell responses in a context-dependent manner. Abnormal Eph receptor and ephrin signaling is implicated in a variety of epithelial diseases raising the intriguing possibility that this cell-cell communication pathway can be therapeutically harnessed to normalize epithelial function in pathological settings like cancer or chronic inflammation.

The physical separation of the embryonic regions that give rise to the tissues and organs of multicellular organisms is a fundamental aspect of morphogenesis. Pioneer experiments by Holtfreter had shown that embryonic cells can sort based on "tissue affinities," which have long been considered to rely on differences in cell-cell adhesion. However, vertebrate embryonic tissues also express a variety of cell surface cues, in particular ephrins and Eph receptors, and there is now firm evidence that these molecules are systematically used to induce local repulsion at contacts between different cell types, efficiently preventing mixing of adjacent cell populations.

Regulation of the activity of N-methyl-d-aspartate receptors (NMDARs) at glutamatergic synapses is essential for certain forms of synaptic plasticity underlying learning and memory and is also associated with neurotoxicity and neurodegenerative diseases. In this report, we investigate the role of Src-like adaptor protein (Slap) in NMDA receptor signaling. We present data showing that in dissociated neuronal cultures, activation of ephrin (Eph) receptors by chimeric preclustered eph-Fc ligands leads to recruitment of Slap and NMDA receptors at the sites of Eph receptor activation. Interestingly, our data suggest that prolonged activation of EphA receptors is as efficient in recruiting Slap and NMDA receptors as prolonged activation of EphB receptors. Using established heterologous systems, we examined whether Slap is an integral part of NMDA receptor signaling. Our results showed that Slap does not alter baseline activity of NMDA receptors and does not affect Src-dependent potentiation of NMDA receptor currents in Xenopus oocytes. We also demonstrate that Slap reduces excitotoxic cell death triggered by activation of NMDARs in HEK293 cells. Finally, we present evidence showing reduced levels of NMDA receptors in the presence of Slap occurring in an activity-dependent manner, suggesting that Slap is part of a mechanism that homeostatically modulates the levels of NMDA receptors.

Eph receptors and their membrane-bound ligands are intimately involved in the control of morphogenic processes during embryonic development and adult tissue homeostasis. By their ability to orchestrate cell migration, pattern formation and tissue integrity they are also prone to be involved in carcinogenic growth. In this review we concentrate on their involvement in the normal and carcinogenic development of the breast. In this context we summarize their multi-faceted functions as tumor suppressors, tumor promoters, angiogenic inducers and regulators of stem cell homeostasis.

Bones cannot properly form or be maintained without cell-cell interactions through ephrin ligands and Eph receptors. Cell culture analysis and evaluation of genetic mouse models and human diseases reveal various ephrins and Eph functions in the skeletal system. Migration, attachment and spreading of mesenchymal stem cells are regulated by ephrinB ligands and EphB receptors. ephrinB1 loss-of-function is associated with craniofrontonasal syndrome (CFNS) in humans and mice. In bone remodeling, ephrinB2 is postulated to act as a "coupling stimulator." In that case, bidirectional signaling between osteoclastic ephrinB2 and osteoblastic EphB4 suppresses osteoclastic bone resorption and enhances osteoblastic bone formation, facilitating the transition between these two states. Parathyroid hormone (PTH) induces ephrinB2 in osteoblasts and enhances osteoblastic bone formation. In contrast to ephrinB2, ephrinA2 acts as a "coupling inhibitor," since ephrinA2 reverse signaling into osteoclasts enhances osteoclastogenesis and EphA2 forward signaling into osteoblasts suppresses osteoblastic bone formation and mineralization. Furthermore, ephrins and Ephs likely modulate pathological conditions such as osteoarthritis, rheumatoid arthritis, multiple myeloma and osteosarcoma. This review focuses on ephrin/Eph-mediated cell-cell interactions in bone biology.

The erythropoietin-producing hepatocellular (Eph) receptors form the largest family of receptor tyrosine kinases. Upon interaction of the Eph receptors with their ligands the ephrins, signaling cascades are initiated downstream of both receptor and ligand, a feature known as bidirectional signaling. The Eph receptors and ephrin ligands mediate important roles in embryonic development, particularly in establishing tissue organization by mediating cell adhesion or cell repulsion. In several adult tissues, at least one Eph/ephrin pair is found to play critical roles in tissue physiology and homeostasis. In recent years numerous members of this family have gained considerable attention since changes in their expression levels are a typical feature in cancer cells. Despite the fact that Eph/ephrin developmental expression profiles are well documented, little is known on transcriptional and post-transcriptional mechanisms that permits their highly specific, graded, complementary or overlapping expression patterns. Therefore understanding the transcriptional and post-transcriptional mechanisms regulating Eph/ephrin expression has far-reaching significance in biology. This review provides an overview of the mechanisms regulating Eph/ephrin expression. We highlight important emerging mechanisms of Eph/ephrin regulation or misregulation such as epigenetics and miRNAs.

The family of Eph tyrosine kinase receptors is an important part of signaling pathways involved in development, tissue homeostasis and tumorigenesis. Binding and activation of the receptors by their ligands, the ephrins, result in bidirectional signaling into both receptor and ligand expressing cells. Adult stem cell niches and tumors frequently express receptors and ligands, although their function is only beginning to be understood. Thus, Eph receptors and ephrins have become important molecules for understanding basic biological processes as well as tumorigenesis, and are promising targets for potential therapeutic intervention in human disease.

A better knowledge of the molecular mechanisms that govern leukocyte trafficking is of major relevance for the clinics. Both normal and pathologic extravasation of lymphocytes are a fine-tuned spatio-temporal event of migratory path-finding likely regulated by molecular guidance cues underlying cell movements in other systems. We have recently reported that members of the Eph family of receptor tyrosine kinases, namely EphA2 and one of its ligands, ephrin-A4 (EFNA4) can mediate in the traffic of chronic lymphocytic leukemia (CLL) cells and presumably of normal B cells between the blood and the tissues. The importance of EphA2-EFNA4 interactions at the endothelium-lymphocyte interface during TEM could rely on their attractive/repulsive properties. In the present work, we expand on those results by including additional insights and new suggestions for future studies that discuss the relevance of these molecules in overall cell adhesion dynamic events.