Eph receptors and ephrins in cancer progression.

Evidence implicating Eph receptor tyrosine kinases and their ephrin ligands (that together make up the 'Eph system') in cancer development and progression has been accumulating since the discovery of the first Eph receptor approximately 35 years ago. Advances in the past decade and a half have considerably increased the understanding of Eph receptor-ephrin signalling mechanisms in cancer and have uncovered intriguing new roles in cancer progression and drug resistance. This Review focuses mainly on these more recent developments. I provide an update on the different mechanisms of Eph receptor-ephrin-mediated cell-cell communication and cell autonomous signalling, as well as on the interplay of the Eph system with other signalling systems. I further discuss recent advances in elucidating how the Eph system controls tumour expansion, invasiveness and metastasis, supports cancer stem cells, and drives therapy resistance. In addition to functioning within cancer cells, the Eph system also mediates the reciprocal communication between cancer cells and cells of the tumour microenvironment. The involvement of the Eph system in tumour angiogenesis is well established, but recent findings also demonstrate roles in immune cells, cancer-associated fibroblasts and the extracellular matrix. Lastly, I discuss strategies under evaluation for therapeutic targeting of Eph receptors-ephrins in cancer and conclude with an outlook on promising future research directions.

Ephrin B/EphB in neuropathic pain: Role and molecular mechanisms.

Ephrins are protein ligands that act through the tyrosine kinase receptor family, Eph receptors. The role of ephrin/Eph in the critical processes involved in the development of the nervous system, including axon guidance and cell migration, has been well documented. Moreover, studies have shown an upregulation of ephrin B1/EphB1 and ephrin B2/EphB2 in neuropathic pain of different etiology. The activation of the ephrin B/EphB system in the dorsal root ganglion and dorsal horn of the spinal cord may be essential in initiating and maintaining neuropathic pain. Accordingly, it can be proposed that the pharmacological inhibitors of EphB receptors may be potentially employed to manage the manifestations of pain. One of the primary mechanisms involved in ephrin B/EphB-mediated synaptic plasticity includes phosphorylation and activation of NMDA receptors, which may be secondary to activation of different kinases, including MAP kinases (MAPK), protein kinase C (PKC), and Src family kinases (SFK). The other molecular mechanisms may include activation of inflammatory cytokines in the spinal cord, caspase-3, calpain-1, phosphoinositide 3-kinase (PI3K), protein kinase A (PKA), and cAMP Response Element-Binding Protein (CREB). The present review discusses the role and molecular mechanisms involved in ephrin B/EphB-mediated neuropathic pain of different etiology.

In silico prediction of interaction between Nipah virus attachment glycoprotein and host cell receptors Ephrin-B2 and Ephrin-B3 in domestic and peridomestic mammals.

Nipah virus (NiV) is a lethal bat-borne zoonotic virus that causes mild to acute respiratory distress and neurological manifestations in humans with a high mortality rate. NiV transmission to humans occurs via consumption of bat-contaminated fruit and date palm sap (DPS), or through direct contact with infected individuals and livestock. Since NiV outbreaks were first reported in pigs from Malaysia and Singapore, non-neutralizing antibodies against NiV attachment Glycoprotein (G) have also been detected in a few domestic mammals. NiV infection is initiated after NiV G binds to the host cell receptors Ephrin-B2 and Ephrin-B3. In this study, we assessed the degree of NiV host tropism in domestic and peridomestic mammals commonly found in Bangladesh that may be crucial in the transmission of NiV by serving as intermediate hosts. We carried out a protein-protein docking analysis of NiV G complexes (n = 52) with Ephrin-B2 and B3 of 13 domestic and peridomestic species using bioinformatics tools. Protein models were generated by homology modelling and the structures were validated for model quality. The different protein-protein complexes in this study were stable, and their binding affinity (ΔG) scores ranged between -8.0 to -19.1 kcal/mol. NiV Bangladesh (NiV-B) strain displayed stronger binding to Ephrin receptors, especially with Ephrin-B3 than the NiV Malaysia (NiV-M) strain, correlating with the observed higher pathogenicity of NiV-B strains. From the docking result, we found that Ephrin receptors of domestic rat (R. norvegicus) had a higher binding affinity for NiV G, suggesting greater susceptibility to NiV infections compared to other study species. Investigations for NiV exposure to domestic/peridomestic animals will help us knowing more the possible role of rats and other animals as intermediate hosts of NiV and would improve future NiV outbreak control and prevention in humans and domestic animals.

Engineered Recombinant EGFP-Azurin Theranostic Nanosystem for Targeted Therapy of Prostate Cancer.

Erythropoietin-producing hepatocellular (Eph) receptors and their ligands, ephrins, are the largest subfamily of receptor tyrosine kinases (RTKs) that have emerged as a new class of cancer biomarkers due to their aberrant expression in cancer progression. The activation of Eph receptors either due to their hyperexpression or via high affinity binding with their respective ephrin ligands initiates a cascade of signals that impacts cancer development and progression. In prostate cancer, the overexpression of the EphA6 receptor has been correlated with increased metastatic potential. Azurin, a small redox protein, is known to prevent tumor progression by binding to cell surface Eph receptors, inhibiting its autophosphorylation in the kinase domain and thereby disrupting Eph-ephrin signaling. Hence, a self-assembled, theranostic nanosystem of recombinant fusion protein his6EGFP-azu (80-128) was designed by conjugating enhanced green fluorescent protein (EGFP) with the C-terminal region of azurin. This design was inspired by the in silico binding study, where the analogue of ephrinA, his6EGFP-azu (80-128) showed higher binding affinity for the EphA6 receptor than the ephrinA ligands. The his6EGFP-azu (80-128) nanosystem which assembled as nanoparticles was tested for its ability to simultaneously detect and kill the prostate cancer cells, LNCaP. This was achieved by specifically targeting EphA6 receptors overexpressed on the cancer cell surface via C-terminal peptide, azu (80-128). Herein, we report antiproliferative, apoptotic, antimigratory, and anti-invasive effects of this nanosystem on LNCaP cells, while having no similar effects on EphA6 negative human normal lung cells, WI-38.

Impaired erythropoietin-producing hepatocellular B receptors signaling in the prefrontal cortex and hippocampus following maternal immune activation in male rats.

An environmental risk factor for schizophrenia (SZ) is maternal infection, which exerts longstanding effects on the neurodevelopment of offspring. Accumulating evidence suggests that synaptic disturbances may contribute to the pathology of the disease, but the underlying molecular mechanisms remain poorly understood. Erythropoietin-producing hepatocellular B (EphB) receptor signaling plays an important role in synaptic plasticity by regulating the formation and maturation of dendritic spines and regulating excitatory neurotransmission. We examined whether EphB receptors and downstream associated proteins are susceptible to environmental risk factors implicated in the etiology of synaptic disturbances in SZ. Using an established rodent model, which closely imitates the characteristics of SZ, we observed the behavioral performance and synaptic structure of male offspring in adolescence and early adulthood. We then analyzed the expression of EphB receptors and associated proteins in the prefrontal cortex and hippocampus. Maternal immune activation offspring showed significantly progressive cognitive impairment and pre-pulse inhibition deficits together with an increase in the expression of EphB2 receptors and NMDA receptor subunits. We also found changes in EphB receptor downstream signaling, in particular, a decrease in phospho-cofilin levels which may explain the reduced dendritic spine density. Besides, we found that the AMPA glutamate, another glutamate ionic receptor associated with cofilin, decreased significantly in maternal immune activation offspring. Thus, alterations in EphB signaling induced by immune activation during pregnancy may underlie disruptions in synaptic plasticity and function in the prefrontal cortex and hippocampus associated with behavioral and cognitive impairment. These findings may provide insight into the mechanisms underlying SZ.

SASH1: A Novel Eph Receptor Partner and Insights into SAM-SAM Interactions.

The Eph (erythropoietin-producing human hepatocellular) receptor family, the largest subclass of receptor tyrosine kinases (RTKs), plays essential roles in embryonic development and neurogenesis. The intracellular Sterile Alpha Motif (SAM) domain presents a critical structural feature that distinguishes Eph receptors from other RTKs and participates in recruiting and binding downstream molecules. This study identified SASH1 (SAM and SH3 domain containing 1) as a novel Eph receptor-binding partner through SAM-SAM domain interactions. Our comprehensive biochemical analyses revealed that SASH1 selectively interacts with Eph receptors via its SAM1 domain, displaying the highest affinity for EphA8. The high-resolution crystal structure of the EphA8-SASH1 complex provided insights into the specific intermolecular interactions between these proteins. Cellular assays confirmed that EphA8 and SASH1 co-localize and co-precipitate in mammalian cells, with cancer mutations (EphA8 R942H or G978D) impairing this interaction. We demonstrated that SAM-SAM interaction is critical for SASH1-mediated regulation of EphA8 kinase activity, shedding new light on the Eph signaling pathway and expanding our understanding of the molecular basis of the tumor suppressor gene SASH1.

Integration of cancer-related genetic landscape of Eph receptors and ephrins with proteomics identifies a crosstalk between EPHB6 and EGFR.

Eph receptors and their ephrin ligands are viewed as promising targets for cancer treatment; however, targeting them is hindered by their context-dependent functionalities. To circumvent this, we explore molecular landscapes underlying their pro- and anti-malignant activities. Using unbiased bioinformatics approaches, we construct a cancer-related network of genetic interactions (GIs) of all Ephs and ephrins to assist in their therapeutic manipulation. We also apply genetic screening and BioID proteomics and integrate them with machine learning approaches to select the most relevant GIs of one Eph receptor, EPHB6. This identifies a crosstalk between EPHB6 and EGFR, and further experiments confirm the ability of EPHB6 to modulate EGFR signaling, enhancing the proliferation of cancer cells and tumor development. Taken together, our observations show EPHB6 involvement in EGFR action, suggesting its targeting might be beneficial in EGFR-dependent tumors, and confirm that the Eph family genetic interactome presented here can be effectively exploited in developing cancer treatment approaches.

The Eph/Ephrin system in primary bone tumor and bone cancer pain.

The family of Eph receptor tyrosine kinases and their Ephrin ligands system constitutes a bidirectional signaling pathway. Eph/Ephrin system coordinate a wide spectrum of pathologic processes during development, metastasis, prognosis, drug resistance and angiogenesis in carcinogenesis. Chemotherapy, surgery and radiotherapy are the most commonly used clinical treatments for primary bone tumors. Therefore, surgical resection is often unable to completely eliminate the tumor, and this is the main cause of metastasis and postoperative recurrence. A growing body of literature has been published lately revitalizing our scientific interest towards the role of Eph/Ephrins in pathogenesis and the treatment of bone tumor and bone cancer pain. This study mainly reviewed the roles of Eph/Ephrin system that has both tumor-suppressing and -promoting roles in primary bone tumors and bone cancer pain. Understanding the intracellular mechanisms of Eph/Ephrin system in tumorigenesis and metastasis of bone tumors might provide a foundation for the development of Eph/Ephrin targeted anti-cancer therapy.

The EPH/Ephrin System in Pancreatic Ductal Adenocarcinoma (PDAC): From Pathogenesis to Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is a major concern for health care systems worldwide, since its mortality remains unaltered despite the surge in cutting-edge science. The EPH/ephrin signaling system was first investigated in the 1980s. EPH/ephrins have been shown to exert bidirectional signaling and cell-to-cell communication, influencing cellular morphology, adhesion, migration and invasion. Recent studies have highlighted the critical role of the EPH/ephrin system in various physiologic processes, including cellular proliferation, survival, synaptic plasticity and angiogenesis. Thus, it has become evident that the EPH/ephrin signaling system may have compelling effects on cell homeostasis that contribute to carcinogenesis. In particular, the EPH/ephrins have an impact on pancreatic morphogenesis and development, whereas several EPHs and ephrins are altered in PDAC. Several clinical and preclinical studies have attempted to elucidate the effects of the EPH/ephrin pathway, with multilayered effects on PDAC development. These studies have highlighted its highly promising role in the diagnosis, prognosis and therapeutic management of PDAC. The aim of this review is to explore the obscure aspects of the EPH/ephrin system concerning the development, physiology and homeostasis of the pancreas.

EphB3 as a Potential Mediator of Developmental and Reparative Osteogenesis.

The ephrin-B family of membrane-bound ligands is involved in skeletal patterning, osteogenesis, and bone homeostasis. Yet, despite the increasing collection of data affirming their importance in bone, the Eph tyrosine kinases that serve as the receptors for these ephrins in osteoblast stem cell niches remain unidentified. Here we report the expression of EphB3 at sites of bone growth in the embryo, especially at the calvaria suture fronts, periosteum, chondrocytes, and trabeculae of developing long bones. Strong EphB3 expression persisted in the adult calvarial sutures and in the proliferative chondrocytes of long bones, both of which are documented niches for osteoblastic stem cells. We observed EphB3-positive cells in the tissue filling a created calvarial injury, further implying EphB3 involvement in bone healing. Genetic knockout of EphB3 caused an increase in the bone tissue volume as a fraction of total volume in 6-week-old calvaria and in femoral trabecular density, compared to wild type controls. This difference resolved by 12 weeks of age, when we instead observed an increase in the bone volume of femoral trabeculae and in trabecular thickness. Our data identify EphB3 as a candidate regulator of osteogenesis either alone or in combination with other bone-expressed Ephs, and indicate that it appears to function as a limiter of bone growth.

Eph and ephrin signaling in the development of the central auditory system.

Acoustic communication relies crucially on accurate interpretation of information about the intensity, frequency, timing, and location of diverse sound stimuli in the environment. To meet this demand, neurons along different levels of the auditory system form precisely organized neural circuits. The assembly of these precise circuits requires tight regulation and coordination of multiple developmental processes. Several groups of axon guidance molecules have proven critical in controlling these processes. Among them, the family of Eph receptors and their ephrin ligands emerge as one group of key players. They mediate diverse functions at multiple levels of the auditory pathway, including axon guidance and targeting, topographic map formation, as well as cell migration and tissue pattern formation. Here, we review our current knowledge of how Eph and ephrin molecules regulate different processes in the development and maturation of central auditory circuits.

The Functions of EphA1 Receptor Tyrosine Kinase in Several Tumors.

BACKGROUND: Eph receptors tyrosine kinase (RTK) were identified in 1987 from hepatocellular carcinoma cell lines and were the largest known subfamily of RTK. Eph receptors can be divided into two categories, EphA and EphB, based on their structure and receptor-ligand specificity. EphA can be divided into 10 species (EphA 1-10) and EphB into 6 species (EphB1-6). Similarly, the ligands of Eph receptors are Ephrins. Ephrins also can be divided into Ephrin A and Ephrin B, of which there are five species(Ephrin-A1-5) and three species(Ephrin-B1-3). Among the Eph receptors, EphA1 has been the least studied so far. As far as we know, Eph receptors are involved in multiple pathologies, including cancer progression, tumor angiogenesis, intestinal environmental stability, the lymph node system, neurological disease, and inhibition of nerve regeneration after injury. There is a link between EphA1, integrin and ECM- related signal pathways. Ephrin-A1 is a ligand of the EphA1 receptor. EphA1 and ephrin-A1 functions are related to tumor angiogenesis. EphA1 and ephrin-A1 also play roles in gynecological diseases. Ephrin-A1 and EphA1 receptors regulate the follicular formation, ovulation, embryo transport, implantation and placental formation, which are of great significance for the occurrence of gynecological tumor diseases. EphA1 has been identified as an oncoprotein in various tumors and has been associated with the prognosis of various tumors in recent years. EphA1 is considered a driver gene in tumor genomics. There are significant differences in EphA1 expression levels in different types of normal tissues and tumors and even in different stages of tumor development, suggesting its functional diversity. Changes at the gene level in cell biology are often used as biological indicators of cancer, known as biomarkers, which can be used to provide diagnostic or prognostic information and are valuable for improving the detection, monitoring and treatment of tumors. However, few prognostic markers can selectively predict clinically significant tumors with poor prognosis. These malignancies are more likely to progress and lead to death, requiring more aggressive treatment. Currently available treatments for advanced cancer are often ineffective, and treatment options are mainly palliative. Therefore, early identification and treatment of those at risk of developing malignant tumors are crucial. Although pieces of evidence have shown the role of EphA1 in tumorigenesis and development, its specific mechanism is still unknown to a great extent. OBJECTIVE: This review reveals the changes and roles of EphA1 in many tumors and cancers. The change of EphA1 expression can be used as a biological marker of cancer, which is valuable for improving tumor detection, monitoring and treatment and can be applied to imaging. Studies have shown that structural modification of EphA1 could make it an effective new drug. EphA1 is unique in that it can be considered a prognostic marker in many tumors and is of important meaning for clinical diagnosis and operative treatment. At the same time, the study of the specific mechanism of EphA1 in tumors can provide a new way for targeted therapy. METHODS: Relevant studies were retrieved and collected through the PubMed system. After determining EphA1 as the research object, by analyzing research articles on EphA1 in the PubMed system in recent 10 years, we found that EphA1 was closely connected with the occurrence and development of tumors and further determined the references according to the influencing factors for review and analysis. RESULTS: EphA1 has been identified as a cancer protein in various tumors, such as hepatocellular carcinoma, nasopharyngeal carcinoma, ovarian cancer, gastric cancer, colorectal cancer, clear cell renal cell carcinoma, esophageal squamous cell carcinoma, breast cancer, prostate cancer and uveal melanoma. EphA1 is abnormally expressed in these tumor cells, which mainly plays a role in cancer progression, tumor angiogenesis, intestinal environmental stability, the lymph node system, nervous system diseases and gynecological diseases. In a narrow sense, EphA1 is especially effective in breast cancer in terms of gynecological diseases. However, the specific mechanism of EphA1 leading to the change of cancer cells in some tumors is not clear, which needs further research and exploration. CONCLUSION: RTK EphA1 can be used as a biomarker for tumor diagnosis (especially a prognostic marker), an indispensable therapeutic target for new anti-tumor therapies, and a novel anti-tumor drug.

A non-coding variant in 5' untranslated region drove up-regulation of pseudo-kinase EPHA10 and caused non-syndromic hearing loss in humans.

Hereditary hearing loss has a genetic and phenotypic heterogeneity. However, it is still difficult to explain this heterogeneity perfectly with known deafness genes. Here, we report a novel causative gene EPHA10 as well as its non-coding variant in 5' untranslated region identified in a family with post-lingual autosomal dominant non-syndromic hearing loss from southern China. One affected member of this family had an ideal hearing restoration after cochlear implantation. We speculated that there were probable deafness-causing abnormalities in the cochlea according to clinical imaging and auditory evaluations. A heterozygous variant c.-81_-73delinsAGC was found co-segregating with hearing loss. Epha10 was expressed in mouse cochlea at both transcription and translation levels. The variant caused upregulation of EPHA10 which may result from promoter activity enhancement after sequence change. Overexpression of Eph (the homolog of human EPHA10) exerted effects on the structure and function of chordotonal organ in fly model. In summary, our study linked pseudo-kinase EPHA10 to hearing loss in humans for the first time.

Signals transduced by Eph receptors and ephrin ligands converge on MAP kinase and AKT pathways in human cancers.

Eph receptors, the largest known family of receptor tyrosine kinases, and ephrin ligands have been implicated in a variety of human cancers. The novel bidirectional signaling events initiated by binding of Eph receptors to their cognate ephrin ligands modulate many cellular processes such as proliferation, metastasis, angiogenesis, invasion, and apoptosis. The relationships between the abundance of a unique subset of Eph receptors and ephrin ligands with associated cellular processes indicate a key role of these molecules in tumorigenesis. The combinatorial expression of these molecules converges on MAP kinase and/or AKT/mTOR signaling pathways. The intracellular target proteins of the initial signal may, however, vary in some cancers. Furthermore, we have also described the commonality of up- and down-regulation of individual receptors and ligands in various cancers. The current state of research in Eph receptors illustrates MAP kinase and mTOR pathways as plausible targets for therapeutic interventions in various cancers.

Kindlin2 enables EphB/ephrinB bi-directional signaling to support vascular development.

Direct contact between cells expressing either ephrin ligands or Eph receptor tyrosine kinase produces diverse developmental responses. Transmembrane ephrinB ligands play active roles in transducing bi-directional signals downstream of EphB/ephrinB interaction. However, it has not been well understood how ephrinB relays transcellular signals to neighboring cells and what intracellular effectors are involved. Here, we report that kindlin2 can mediate bi-directional ephrinB signaling through binding to a highly conserved NIYY motif in the ephrinB2 cytoplasmic tail. We show this interaction is important for EphB/ephrinB-mediated integrin activation in mammalian cells and for blood vessel morphogenesis during zebrafish development. A mixed two-cell population study revealed that kindlin2 (in ephrinB2-expressing cells) modulates transcellular EphB4 activation by promoting ephrinB2 clustering. This mechanism is also operative for EphB2/ephrinB1, suggesting that kindlin2-mediated regulation is conserved for EphB/ephrinB signaling pathways. Together, these findings show that kindlin2 enables EphB4/ephrinB2 bi-directional signal transmission.

EPH/Ephrin-Targeting Treatment in Breast Cancer: A New Chapter in Breast Cancer Therapy.

Breast cancer (BC) is the most common malignant tumor in women. Erythropoietin-producing hepatocellular receptors (EPHs), receptor tyrosine kinases binding the membrane-bound proteins ephrins, are differentially expressed in BC, and correlate with carcinogenesis and tumor progression. With a view to examining available therapeutics targeting the EPH/ephrin system in BC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most studied EPH/ephrin target in BC treatment. The targeting of EPHA2, EPHA10, EPHB4, ephrin-A2, ephrin-A4, as well as ephrin-B2 in BC cells or xenograft models is associated with apoptosis induction, tumor regression, anticancer immune response activation, and impaired cell motility. In conclusion, EPHs/ephrins seem to represent promising future treatment targets in BC.

Altered thymocyte development observed in EphA4-deficient mice courses with changes in both thymic epithelial and extracellular matrix organization.

Eph receptors and their ligands, Ephrins, are involved in the thymocyte-thymic epithelial cell (TEC) interactions, key for the functional maturation of both thymocytes and thymic epithelium. Several years ago, we reported that the lack of EphA4, a Eph of the subfamily A, coursed with reduced proportions of double positive (DP) thymocytes apparently due to an altered thymic epithelial stroma [Munoz et al. in J Immunol 177:804-813, 2006]. In the present study, we reevaluate the lymphoid, epithelial, and extracellular matrix (ECM) phenotype of EphA4-/- mice grouped into three categories with respect to their proportions of DP thymocytes. Our results demonstrate a profound hypocellularity, specific alterations of T cell differentiation that affected not only DP thymocytes, but also double negative and single positive T cell subsets, as well as the proportions of positively and negatively selected thymocytes. In correlation, thymic histological organization changed markedly, especially in the cortex, as well as the proportions of both Ly51+UEA-1- cortical TECs and Ly51-UEA-1+ medullary TECs. The alterations observed in the expression of ECM components (Fibronectin, Laminin, Collagen IV), integrin receptors (VLA-4, VLA-6), chemokines (CXCL12, CCL25, CCL21) and their receptors (CXCR4, CCR7, CCR9) and in vitro transwell assays on the capacity of migration of WT and mutant thymocytes suggest that the lack of EphA4 alters T-cell differentiation by presumably affecting cell adhesion between TECs and T-TEC interactions rather than by thymocyte migration.

Mapping the Universe of Eph Receptor and Ephrin Ligand Transcripts in Epithelial and Fiber Cells of the Eye Lens.

The eye lens is a transparent, ellipsoid organ in the anterior chamber of the eye that is required for fine focusing of light onto the retina to transmit a clear image. Cataracts, defined as any opacity in the lens, remains the leading cause of blindness in the world. Recent studies in humans and mice indicate that Eph-ephrin bidirectional signaling is important for maintaining lens transparency. Specifically, mutations and polymorphisms in the EphA2 receptor and the ephrin-A5 ligand have been linked to congenital and age-related cataracts. It is unclear what other variants of Ephs and ephrins are expressed in the lens or whether there is preferential expression in epithelial vs. fiber cells. We performed a detailed analysis of Eph receptor and ephrin ligand mRNA transcripts in whole mouse lenses, epithelial cell fractions, and fiber cell fractions using a new RNA isolation method. We compared control samples with EphA2 knockout (KO) and ephrin-A5 KO samples. Our results revealed the presence of transcripts for 12 out of 14 Eph receptors and 8 out of 8 ephrin ligands in various fractions of lens cells. Using specific primer sets, RT-PCR, and sequencing, we verified the variant of each gene that is expressed, and we found two epithelial-cell-specific genes. Surprisingly, we also identified one Eph receptor variant that is expressed in KO lens fibers but is absent from control lens fibers. We also identified one low expression ephrin variant that is only expressed in ephrin-A5 control samples. These results indicate that the lens expresses almost all Ephs and ephrins, and there may be many receptor-ligand pairs that play a role in lens homeostasis.

Neuronal Guidance Molecules in Bone Remodeling and Orthodontic Tooth Movement.

During orthodontic tooth movement, mechanically induced remodeling occurs in the alveolar bone due to the action of orthodontic forces. The number of factors identified to be involved in mechanically induced bone remodeling is growing steadily. With the uncovering of the functions of neuronal guidance molecules (NGMs) for skeletal development as well as for bone homeostasis, NGMs are now also among the potentially significant factors for the regulation of bone remodeling during orthodontic tooth movement. This narrative review attempts to summarize the functions of NGMs in bone homeostasis and provides insight into the currently sparse literature on the functions of these molecules during orthodontic tooth movement. Presently, four families of NGMs are known: Netrins, Slits, Semaphorins, ephrins and Eph receptors. A search of electronic databases revealed roles in bone homeostasis for representatives from all four NGM families. Functions during orthodontic tooth movement, however, were only identified for Semaphorins, ephrins and Eph receptors. For these, crucial prerequisites for participation in the regulation of orthodontically induced bone remodeling, such as expression in cells of the periodontal ligament and in the alveolar bone, as well as mechanical inducibility, were shown, which suggests that the importance of NGMs in orthodontic tooth movement may be underappreciated to date and further research might be warranted.

EPH receptor tyrosine kinases phosphorylate the PAR-3 scaffold protein to modulate downstream signaling networks.

EPH receptors (EPHRs) constitute the largest family among receptor tyrosine kinases in humans. They are mainly involved in short-range cell-cell communication events that regulate cell adhesion, migration, and boundary formation. However, the molecular mechanisms by which EPHRs control these processes are less understood. To address this, we unravel EPHR-associated complexes under native conditions using mass-spectrometry-based BioID proximity labeling. We obtain a composite proximity network from EPHA4, -B2, -B3, and -B4 that comprises 395 proteins, most of which were not previously linked to EPHRs. We examine the contribution of several BioID-identified candidates via loss-of-function in an EPHR-dependent cell-segregation assay. We find that the signaling scaffold PAR-3 is required for cell sorting and that EPHRs directly phosphorylate PAR-3. We also delineate a signaling complex involving the C-terminal SRC kinase (CSK), whose recruitment to PAR-3 is dependent on EPHR signals. Our work describes signaling networks by which EPHRs regulate cellular phenotypes.