scholarly journals Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina

Development ◽  
2000 ◽  
Vol 127 (6) ◽  
pp. 1231-1241 ◽  
Author(s):  
E. Birgbauer ◽  
C.A. Cowan ◽  
D.W. Sretavan ◽  
M. Henkemeyer
Keyword(s):  
Optic Disc ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Retinal Development ◽  
Mouse Retina ◽  
Target Cells ◽  
Eph Receptors ◽  
Axon Pathfinding ◽  
Embryonic Mouse ◽  
Ephb Receptors

Optic nerve formation requires precise retinal ganglion cell (RGC) axon pathfinding within the retina to the optic disc, the molecular basis of which is not well understood. At CNS targets, interactions between Eph receptor tyrosine kinases on RGC axons and ephrin ligands on target cells have been implicated in formation of topographic maps. However, studies in chick and mouse have shown that both Eph receptors and ephrins are also expressed within the retina itself, raising the possibility that this receptor-ligand family mediates aspects of retinal development. Here, we more fully document the presence of specific EphB receptors and B-ephrins in embryonic mouse retina and provide evidence that EphB receptors are involved in RGC axon pathfinding to the optic disc. We find that as RGC axons begin this pathfinding process, EphB receptors are uniformly expressed along the dorsal-ventral retinal axis. This is in contrast to the previously reported high ventral-low dorsal gradient of EphB receptors later in development when RGC axons map to CNS targets. We show that mice lacking both EphB2 and EphB3 receptor tyrosine kinases, but not each alone, exhibit increased frequency of RGC axon guidance errors to the optic disc. In these animals, major aspects of retinal development and cellular organization appear normal, as do the expression of other RGC guidance cues netrin, DCC, and L1. Unexpectedly, errors occur in dorsal but not ventral retina despite early uniform or later high ventral expression of EphB2 and EphB3. Furthermore, embryos lacking EphB3 and the kinase domain of EphB2 do not show increased errors, consistent with a guidance role for the EphB2 extracellular domain. Thus, while Eph kinase function is involved in RGC axon mapping in the brain, RGC axon pathfinding within the retina is partially mediated by EphB receptors acting in a kinase-independent manner.

scholarly journals Antibody Targeting of Eph Receptors in Cancer

2020 ◽  
Vol 13 (5) ◽  
pp. 88
Author(s):  
Peter W. Janes ◽  
Mary E. Vail ◽  
Hui K. Gan ◽  
Andrew M. Scott
Keyword(s):  
Tumor Microenvironment ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Communication ◽  
Eph Receptors ◽  
Preclinical Models ◽  
Anti Cancer ◽  
Tumor Specificity ◽  
Mediate Cell ◽  
Cancer Activity

The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with tumor initiation, angiogenesis and metastasis. Eph receptors are thus attractive therapeutic targets, and monoclonal antibodies have been commonly developed and tested for anti-cancer activity in preclinical models, and in some cases in the clinic. This review summarizes 20 years of research on various antibody-based approaches to target Eph receptors in tumors and the tumor microenvironment, including their mode of action, tumor specificity, and efficacy in pre-clinical and clinical testing.

Bidirectional signaling of ErbB and Eph receptors at synapses

2008 ◽  
Vol 4 (3) ◽  
pp. 211-221 ◽  
Author(s):  
Yu Chen ◽  
Amy K.Y. Fu ◽  
Nancy Y. Ip
Keyword(s):  
Neural Development ◽  
Tyrosine Kinases ◽  
Synapse Formation ◽  
Receptor Tyrosine Kinases ◽  
Eph Receptors ◽  
Surface Receptors ◽  
Reverse Signaling ◽  
Synaptic Functions ◽  
Bidirectional Signaling ◽  
Spine Morphogenesis

Synapse development and remodeling are regulated by a plethora of molecules such as receptor tyrosine kinases (RTKs), a family of cell surface receptors that play critical roles in neural development. Two families of RTKs implicated in synaptic functions, ErbBs and Ephs, share similar characteristics in terms of exhibiting forward and reverse signaling. In this review, we will discuss the latest advances in the functions of ErbBs and Ephs at the synapse, including dendritic spine morphogenesis, synapse formation and maturation, and synaptic transmission and plasticity. In addition to signaling at interneuronal synapses, communication between neuron and glia is increasingly implicated in the control of synaptic functions. Studies on RTKs and their cognate ligands in glial cells enhance our understanding on the nature of ‘tripartite synapse’. Implications of these signaling events in human diseases will be discussed.

Dancing with the dead: Eph receptors and their kinase-null partnersThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process.

2011 ◽  
Vol 89 (2) ◽  
pp. 115-129 ◽  
Author(s):  
Luke Truitt ◽  
Andrew Freywald
Keyword(s):  
Membrane Proteins ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Receptor Tyrosine Kinases ◽  
Peer Review Process ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Biological Responses ◽  
Wide Range ◽  
Multicellular Organisms

Eph receptor tyrosine kinases and their ligands, ephrins, are membrane proteins coordinating a wide range of biological functions both in developing embryos and in adult multicellular organisms. Numerous studies have implicated Eph receptors in the induction of opposing responses, including cell adhesion or repulsion, support or inhibition of cell proliferation and cell migration, and progression or suppression of multiple malignancies. Similar to other receptor tyrosine kinases, Eph receptors rely on their ability to catalyze tyrosine phosphorylation for signal transduction. Interestingly, however, Eph receptors also actively utilize three kinase-deficient receptor tyrosine kinases, EphB6, EphA10, and Ryk, in their signaling network. The accumulating evidence suggests that the unusual flexibility of the Eph family, allowing it to initiate antagonistic responses, might be partially explained by the influence of the kinase-dead participants and that the exact outcome of an Eph-mediated action is likely to be defined by the balance between the signaling of catalytically potent and catalytically null receptors. We discuss in this minireview the emerging functions of the kinase-dead EphB6, EphA10, and Ryk receptors both in normal biological responses and in malignancy, and analyze currently available information related to the molecular mechanisms of their action in the context of the Eph family.

Eph receptors and ephrins: effectors of morphogenesis

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2033-2044 ◽  
Author(s):  
N. Holder ◽  
R. Klein
Keyword(s):  
Cell Migration ◽  
Pattern Formation ◽  
Axon Guidance ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Eph Receptors ◽  
Structural Domains ◽  
Eph Receptor

Eph receptor tyrosine kinases and their ligands, the ephrins, appear to lie functionally at the interface between pattern formation and morphogenesis. We review the role of Eph and ephrin signalling in the formation of segmented structures, in the control of axon guidance and cell migration and in the development of the vasculature. We address the question of how the specificity of response is achieved and discuss the specificity of ephrin-Eph interactions and the significance of structural domains in Eph receptors.

Targeting of host cell receptor tyrosine kinases by intracellular pathogens

2019 ◽  
Vol 12 (599) ◽  
pp. eaau9894 ◽  
Author(s):  
Gholamreza Haqshenas ◽  
Christian Doerig
Keyword(s):  
Host Cell ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cell Receptor ◽  
Host Cells ◽  
Target Cells ◽  
Intracellular Pathogens ◽  
Host Cell Receptor ◽  
Host Signaling ◽  
Mediate Cell

Intracellular pathogens use complex and tightly regulated processes to enter host cells. Upon initial interactions with signaling proteins at the surface of target cells, intracellular microbes activate and co-opt specific host signaling pathways that mediate cell surface–cytosol communications to facilitate pathogen internalization. Here, we discuss the roles of host receptor tyrosine kinases (RTKs) in the establishment of productive infections by major intracellular pathogens. We evaluate the gaps in the current understanding of this process and propose a comprehensive approach for assessing the role of host cell signaling in the biology of intracellular microorganisms and viruses. We also discuss RTK-targeting strategies for the treatment of various infections.

scholarly journals EphA7 Functions as Receptor on BJAB Cells for Cell-to-Cell Transmission of the Kaposi's Sarcoma-Associated Herpesvirus and for Cell-Free Infection by the Related Rhesus Monkey Rhadinovirus

2019 ◽  
Vol 93 (15) ◽  
Author(s):  
Anna K. Großkopf ◽  
Sarah Schlagowski ◽  
Bojan F. Hörnich ◽  
Thomas Fricke ◽  
Ronald C. Desrosiers ◽  
...  
Keyword(s):  
Rhesus Monkey ◽  
B Cell ◽  
Tyrosine Kinases ◽  
Kaposi's Sarcoma ◽  
Receptor Tyrosine Kinases ◽  
Kaposi’S Sarcoma ◽  
Target Cells ◽  
Cell Infection ◽  
Eph Receptor ◽  
Glycoprotein Complex

ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma and is associated with two B cell malignancies, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman’s disease. On several adherent cell types, EphA2 functions as a cellular receptor for the gH/gL glycoprotein complex of KSHV. KSHV gH/gL also has previously been found to interact weakly with other members of the Eph family of receptor tyrosine kinases (Ephs), and other A-type Ephs have been shown to be able to compensate for the absence of EphA2 using overexpression systems. However, whether these interactions are of functional consequence at endogenous protein levels has remained unclear so far. Here, we demonstrate for the first time that endogenously expressed EphA7 in BJAB B cells is critical for the cell-to-cell transmission of KSHV from producer iSLK cells to BJAB target cells. The BJAB lymphoblastoid cell line often serves as a model for B cell infection and expresses only low levels of all Eph family receptors other than EphA7. Endogenous EphA7 could be precipitated from the cellular lysate of BJAB cells using recombinant gH/gL, and knockout of EphA7 significantly reduced transmission of KSHV into BJAB target cells. Knockout of EphA5, the second most expressed A-type Eph in BJAB cells, had a similar, although less pronounced, effect on KSHV infection. Receptor function of EphA7 was conserved for cell-free infection by the related rhesus monkey rhadinovirus (RRV), which is relatively even more dependent on EphA7 for infection of BJAB cells.IMPORTANCEInfection of B cells is relevant for two KSHV-associated malignancies, the plasmablastic variant of multicentric Castleman’s disease and PEL. Therefore, elucidating the process of B cell infection is important for the understanding of KSHV pathogenesis. While the high-affinity receptor for the gH/gL glycoprotein complex, EphA2, has been shown to function as an entry receptor for various types of adherent cells, the gH/gL complex can also interact with other Eph receptor tyrosine kinases with lower avidity. We analyzed the Eph interactions required for infection of BJAB cells, a model for B cell infection by KSHV. We identified EphA7 as the principal Eph receptor for infection of BJAB cells by KSHV and the related rhesus monkey rhadinovirus. While two analyzed PEL cell lines exhibited high EphA2 and low EphA7 expression, a third PEL cell line, BCBL-1, showed high EphA7 and low EphA2 expression, indicating a possible relevance for KSHV pathology.

Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4431-4440 ◽  
Author(s):  
Blandine de Saint-Vis ◽  
Caroline Bouchet ◽  
Grégory Gautier ◽  
Jenny Valladeau ◽  
Christophe Caux ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Langerhans Cells ◽  
Receptor Tyrosine Kinases ◽  
Ex Vivo ◽  
Pcr Analysis ◽  
Epidermal Keratinocytes ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Human Dendritic Cells

AbstractEph receptor tyrosine kinases and their ligands, the ephrins, have been primarily described in the nervous system for their roles in axon guidance, development, and cell intermingling. Here we address whether Eph receptors may also regulate dendritic cell (DC) trafficking. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that DCs derived from CD34+ progenitors, but not from monocytes, expressed several receptors, in particular EphA2, EphA4, EphA7, EphB1, and EphB3 mRNA. EphB3 was specifically expressed by Langerhans cells, and EphA2 and EphA7 were expressed by both Langerhans- and interstitial-type DCs. EphA and EphB protein expression on DCs generated in vitro was confirmed by staining with ephrin-A3-Fc and ephrin-B3-Fc fusion proteins that bind to different Eph members, in particular EphA2 and EphB3. Immunostaining with anti-EphA2 antibodies demonstrated the expression of EphA2 by immature DCs and by skin Langerhans cells isolated ex vivo. Interestingly, ephrin expression was detected in epidermal keratinocytes and also in DCs. Adhesion of CD34+-derived DCs to fibronectin, but not to poly-l-lysine, was increased in the presence of ephrin-A3-Fc, a ligand of EphA2, through a β1 integrin activation pathway. As such, EphA2/ephrin-A3 interactions may play a role in the localization and network of Langerhans cells in the epithelium and in the regulation of their trafficking. (Blood. 2003;102:4431-4440)

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