scholarly journals Exosomes mediate cell contact–independent ephrin-Eph signaling during axon guidance

2016 ◽  
Vol 214 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Jingyi Gong ◽  
Roman Körner ◽  
Louise Gaitanos ◽  
Rüdiger Klein
Keyword(s):  
Neural Development ◽  
Tyrosine Kinases ◽  
Neuronal Development ◽  
Cell Types ◽  
Cell Contact ◽  
Eph Receptor ◽  
Endosomal Sorting ◽  
Ephrin Ligands ◽  
Direct Cell ◽  
Mediate Cell

The cellular release of membranous vesicles known as extracellular vesicles (EVs) or exosomes represents a novel mode of intercellular communication. Eph receptor tyrosine kinases and their membrane-tethered ephrin ligands have very important roles in such biologically diverse processes as neuronal development, plasticity, and pathological diseases. Until now, it was thought that ephrin-Eph signaling requires direct cell contact. Although the biological functions of ephrin-Eph signaling are well understood, our mechanistic understanding remains modest. Here we report the release of EVs containing Ephs and ephrins by different cell types, a process requiring endosomal sorting complex required for transport (ESCRT) activity and regulated by neuronal activity. Treatment of cells with purified EphB2+ EVs induces ephrinB1 reverse signaling and causes neuronal axon repulsion. These results indicate a novel mechanism of ephrin-Eph signaling independent of direct cell contact and proteolytic cleavage and suggest the participation of EphB2+ EVs in neural development and synapse physiology.

scholarly journals EphB2 and EphB4 receptors forward signaling promotes SDF-1–induced endothelial cell chemotaxis and branching remodeling

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 2914-2922 ◽  
Author(s):  
Ombretta Salvucci ◽  
Maria de la Luz Sierra ◽  
Jose A. Martina ◽  
Peter J. McCormick ◽  
Giovanna Tosato
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cell ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Cell Movement ◽  
Cell Contact ◽  
Eph Receptor ◽  
Cell Clustering ◽  
Chemokine Ligand ◽  
Ephrin Ligands

Abstract The complex molecular mechanisms that drive endothelial cell movement and the formation of new vessels are poorly understood and require further investigation. Eph receptor tyrosine kinases and their membrane-anchored ephrin ligands regulate cell movements mostly by cell–cell contact, whereas the G-protein–coupled receptor CXCR4 and its unique SDF-1 chemokine ligand regulate cell movement mostly through soluble gradients. By using biochemical and functional approaches, we investigated how ephrinB and SDF-1 orchestrate endothelial cell movement and morphogenesis into capillary-like structures. We describe how endogenous EphB2 and EphB4 signaling are required for the formation of extracellular matrix–dependent capillary-like structures in primary human endothelial cells. We further demonstrate that EphB2 and EphB4 activation enhance SDF-1–induced signaling and chemotaxis that are also required for extracellular matrix–dependent endothelial cell clustering. These results support a model in which SDF-1 gradients first promote endothelial cell clustering and then EphB2 and EphB4 critically contribute to subsequent cell movement and alignment into cord-like structures. This study reveals a requirement for endogenous Eph signaling in endothelial cell morphogenic processes, uncovers a novel link between EphB forward signaling and SDF-1–induced signaling, and demonstrates a mechanism for cooperative regulation of endothelial cell movement.

scholarly journals Roles of Eph receptors and ephrins in segmental patterning

2000 ◽  
Vol 355 (1399) ◽  
pp. 993-1002 ◽  
Author(s):  
Qiling Xu ◽  
Georg Mellitzer ◽  
David G. Wilkinson
Keyword(s):  
Cell Adhesion ◽  
Tyrosine Kinases ◽  
Cell Communication ◽  
Cell Contact ◽  
Eph Receptors ◽  
Biochemical Basis ◽  
Eph Receptor ◽  
Mediate Cell ◽  
Glycosylphosphatidyl Inositol

Eph receptor tyrosine kinases and their membrane–bound ligands, ephrins, have key roles in patterning and morphogenesis. Interactions between these molecules are promiscuous, but largely fall into two groups: EphA receptors bind to glycosylphosphatidyl inositol–anchored ephrin–A ligands, and EphB receptors bind to transmembrane ephrin–B proteins. Ephrin–B proteins transduce signals, such that bidirectional signalling can occur upon interaction with the Eph receptor. In many tissues, there are complementary and overlapping expression domains of interacting Eph receptors and ephrins. An important role of Eph receptors and ephrins is to mediate cell contact–dependent repulsion, and this has been implicated in the pathfinding of axons and neural crest cells, and the restriction of cell intermingling between hindbrain segments. Studies in an in vitro system show that bidirectional activation is required to prevent intermingling between cell populations, whereas unidirectional activation can restrict cell communication via gap junctions. Recent work indicates that Eph receptors can also upregulate cell adhesion, but the biochemical basis of repulsion versus adhesion responses is unclear. Eph receptors and ephrins have thus emerged as key regulators that, in parallel with cell adhesion molecules, underlie the establishment and maintenance of patterns of cellular organization.

Eph Receptor Tyrosine Kinases and Ephrin Ligands Are Epigenetically Inactivated in Acute Lymphoblastic Leukemia and Are Potential New Tumor Suppressor Genes in Human Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2128-2128 ◽  
Author(s):  
Shao-qing Kuang ◽  
Zhi-Hong Fang ◽  
Gonzalo Lopez ◽  
Weigang Tong ◽  
Hui Yang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Leukemia Cell ◽  
Human Leukemia ◽  
Eph Receptor ◽  
Leukemia Cell Lines ◽  
Ephrin Ligands ◽  
Aberrant Dna Methylation

Abstract The Eph (erythroprotein-producing hepatoma amplified sequence) family receptor tyrosine kinases and their ephrin ligands (ephrins) are involved in a variety of functions in normal cell development and cancer. We have identified several members of this family as potential targets of aberrant DNA methylation using Methylated CpG Island Amplification (MCA) / DNA promoter microarray technology. This is of importance as there are no prior reports of potential Eph receptor or Ephrin epigenetic inactivation in human leukemia. To further investigate the role of Eph receptor and ephrin family genes in leukemia, we have analyzed their DNA methylation status in a panel of 23 leukemia cell lines and 65 primary ALL patient samples. Aberrant DNA methylation of 9 of these genes (EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3) was detected in multiple leukemia cell lines but not in normal samples by bisulfite pyrosequencing. In ALL patient samples, the frequencies of DNA methylation detected in the promoter regions of these genes ranged from 23% to 87% for EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3. Expression analysis of 3 of these genes (EPHA5, EPHB4 and Ephrin B2) in leukemia cell lines by real-time PCR further confirmed methylation associated gene silencing. Treatment of methylated/silenced cell lines with DNA methyltransferase inhibitor 5′-aza-2′-deoxycytidine resulted in gene re-expression. Forced overexpression of EPHB4 using a lentivirus transduction system in Raji cell lines resulted in decreased cell proliferation and adhesion-independent cell growth, as well as in an increase in staurosporine induction of apoptosis. In addition, EPHB4 overexpression resulted in a significant downregulation of phosphorylated Akt pathway but had no effect on mitogen-activated protein kinase pathway. In summary, we describe for the first time the epigenetic suppression of Ephrin receptors and their ligands in human leukemia, indicating that these genes may be potential tumor suppressors in leukemia. Targeting of these pathways may result in the development of new potential therapies and biomarkers for patients with ALL.

scholarly journals Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by EphB2

2017 ◽  
Vol 28 (24) ◽  
pp. 3532-3541 ◽  
Author(s):  
Fumihiko Okumura ◽  
Akiko Joo-Okumura ◽  
Keisuke Obara ◽  
Alexander Petersen ◽  
Akihiko Nishikimi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Receptor Tyrosine Kinases ◽  
Cancer Development ◽  
Tyrosine Kinase Activity ◽  
Eph Receptor ◽  
Ephrin Ligands ◽  
Dependent Cell ◽  
Socs Box

Eph receptor tyrosine kinases and their ephrin ligands are overexpressed in various human cancers, including colorectal malignancies, suggesting important roles in many aspects of cancer development and progression as well as in cellular repulsive responses. The ectodomain of EphB2 receptor is cleaved by metalloproteinases (MMPs) MMP-2/MMP-9 and released into the extracellular space after stimulation by its ligand. The remaining membrane-associated fragment is further cleaved by the presenilin-dependent γ-secretase and releases an intracellular peptide that has tyrosine kinase activity. Although the cytoplasmic fragment is degraded by the proteasome, the responsible ubiquitin ligase has not been identified. Here, we show that SOCS box-containing protein SPSB4 polyubiquitinates EphB2 cytoplasmic fragment and that SPSB4 knockdown stabilizes the cytoplasmic fragment. Importantly, SPSB4 down-regulation enhances cell repulsive responses mediated by EphB2 stimulation. Altogether, we propose that SPSB4 is a previously unidentified ubiquitin ligase regulating EphB2-dependent cell repulsive responses.

Complex expression patterns of Eph receptor tyrosine kinases and their ephrin ligands in colorectal carcinogenesis

2012 ◽  
Vol 48 (5) ◽  
pp. 753-762 ◽  
Author(s):  
Nirmitha I. Herath ◽  
Mark D. Spanevello ◽  
James D. Doecke ◽  
Fiona M. Smith ◽  
Celio Pouponnot ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Expression Patterns ◽  
Colorectal Carcinogenesis ◽  
Eph Receptor ◽  
Ephrin Ligands ◽  
Complex Expression

Platelet interaction with vascular smooth muscle in synthesis of prostacyclin

1991 ◽  
Vol 260 (5) ◽  
pp. H1544-H1551
Author(s):  
D. H. Hechtman ◽  
M. H. Kroll ◽  
M. A. Gimbrone ◽  
A. I. Schafer
Keyword(s):  
Smooth Muscle ◽  
Platelet Aggregation ◽  
Vascular Smooth Muscle ◽  
Cell Types ◽  
Arterial Injury ◽  
Rat Aorta ◽  
Cell Contact ◽  
Ionophore A23187 ◽  
Inhibit Platelet Aggregation ◽  
Direct Cell

Because vascular smooth muscle cells (SMC) can be exposed to platelets at sites of significant arterial injury, we studied whether cultured rat aorta SMC can utilize platelet-derived arachidonate and prostaglandin (PG) endoperoxides (PGG2/PGH2) in the synthesis of prostacyclin (PGI2). SMC converted exogenous PGH2 to PGI2, measured by radioimmunoassay (RIA) of 6-keto-PGF1 alpha, despite cyclooxygenase inhibition or PGH2-receptor blockade. SMC produced increasing amounts of PGI2 in the presence of an increasing number of platelets when the two cell types were coincubated with arachidonate. Furthermore, aspirin-pretreated SMC produced PGI2 in response to arachidonate, ionophore A23187, or thrombin in the presence of platelets but not in their absence. SMC, by themselves unresponsive to thrombin, produced PGI2 during coincubation with thrombin-stimulated aspirin-pretreated platelets. Separation of the SMC monolayer and platelets with a filter did not prevent platelet-dependent PGI2 formation by the SMC. Finally, aspirin-pretreated SMC, in cosuspension with platelets, inhibited platelet aggregation in association with PGI2 production. These data indicate that 1) SMC can synthesize PGI2 from exogenously added PGH2 and from platelet-derived arachidonate or endoperoxides, 2) direct cell-cell contact is not required for intercellular endoperoxide transfer, and 3) SMC can inhibit platelet aggregation possibly through PGI2 production from platelet-derived endoperoxides.

Dictyostelium amoebae can differentiate into spores without cell-to-cell contact

Development ◽  
1981 ◽  
Vol 62 (1) ◽  
pp. 369-378
Author(s):  
Robert R. Kay ◽  
David J. Trevan
Keyword(s):  
Cyclic Amp ◽  
Dictyostelium Discoideum ◽  
Time Lapse ◽  
Cell Types ◽  
Spore Formation ◽  
Cellular Interaction ◽  
Cell Contact ◽  
Direct Cell ◽  
Petri Dishes ◽  
Intermediate Density

Amoebae of sporogenous mutants of Dictyostelium discoideum can differentiate into stalk cells and spores in the absence of normal morphogenesis when spread on agar containing cyclic-AMP. The efficiency of differentiation is improved when the amoebae are incubated as submerged monolayers in plastic petri dishes. Under these conditions spore formation is density dependent and hence requires some form of cellular interaction. To determine whether this interaction involves direct cell—cell contact we have made time-lapse films of cells differentiating at intermediate density. These films show that amoebae can develop into spores without making contact with any other cells. In addition, although some cells do divide during incubation, division is not necessary for spore formation. At higher densities small aggregates form which give rise to mixtures of stalk cells and spores. There is no detectable patterning of the two cell types within such aggregates.

Structures of an Eph receptor tyrosine kinase and its potential activation mechanism

2014 ◽  
Vol 70 (12) ◽  
pp. 3135-3143 ◽  
Author(s):  
Qiang Wei ◽  
Jun Liu ◽  
Nan Wang ◽  
Xiaoying Zhang ◽  
Jin Jin ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Tyrosine Kinases ◽  
Activation Mechanism ◽  
Activation Loop ◽  
Eph Receptor ◽  
Kinase Activation ◽  
Active Structures ◽  
Enzyme Substrate ◽  
Alternative Conformation ◽  
Ephrin Ligands

Eph receptor tyrosine kinases (RTKs) and their ephrin ligands play a crucial role in both physiological and pathophysiological processes, including tumourigenesis. A previous study of Eph RTKs established a regulatory role for the juxtamembrane segment (JMS) in kinase activation through the phosphorylation of two tyrosines within the JMS. Here, structures of EphA2 representing various activation states are presented. By determining the unphosphorylated inactive and phosphorylated active structures as well as an alternative conformation, conformational changes during kinase activation have been revealed. It is shown that phosphorylation of a tyrosine residue (Tyr772) in the activation loop without direct involvement of the JMS is sufficient to activate the EphA2 kinase. This mechanistic finding is in contrast to the mechanism of other Eph RTKs, such as EphB2, in which phosphorylation of the two JMS tyrosines initiates the dissociation of the JMS and triggers activation-loop phosphorylation for kinase activation. Furthermore, experiments demonstrate that the EphA2 substrate PTEN, a phosphatase that has been implicated in tumour suppression, acts to regulate the phosphorylation states of EphA2, exemplifying a unique reciprocal enzyme–substrate system. Based on these studies, it is therefore suggested that EphA2 may possess an alternate activation mechanism distinct from other Eph RTKs.

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