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

Gong, Jingyi; Körner, Roman; Gaitanos, Louise; Klein, Rüdiger

doi:10.1083/jcb.201601085

Cited by 111 publications

(106 citation statements)

References 43 publications

(59 reference statements)

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“…The tyrosine kinase receptor Eph and its ligand are secreted by different cell types and regulate neuronal activity. Exosomes that contain Eph receptor cause axonal repulsion, providing support for the role of transmembrane proteins in transcellular exchange . However, additional evidence is required to clarify the potential role of exosomes in the control of axonal proteostasis and in particular the transmembrane proteome.…”

Section: The Role Of Supporting Cells In Axonal Proteostasismentioning

confidence: 99%

Global and local mechanisms sustain axonal proteostasis of transmembrane proteins

Cornejo

Luarte

Couve

2017

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The control of neuronal protein homeostasis or is tightly regulated both spatially and temporally, assuring accurate and integrated responses to external or intrinsic stimuli. Local or autonomous responses in dendritic and axonal compartments are crucial to sustain function during development, physiology and in response to damage or disease. Axons are responsible for generating and propagating electrical impulses in neurons, and the establishment and maintenance of their molecular composition are subject to extreme constraints exerted by length and size. Proteins that require the secretory pathway, such as receptors, transporters, ion channels or cell adhesion molecules, are fundamental for axonal function, but whether axons regulate their abundance autonomously and how they achieve this is not clear. Evidence supports the role of three complementary mechanisms to maintain proteostasis of these axonal proteins, namely vesicular transport, local translation and trafficking and transfer from supporting cells. Here, we review these mechanisms, their molecular machineries and contribution to neuronal function. We also examine the signaling pathways involved in local translation and their role during development and nerve injury. We discuss the relative contributions of a transport-controlled proteome directed by the soma (global regulation) versus a local-controlled proteome based on local translation or cell transfer (local regulation).

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Section: The Role Of Supporting Cells In Axonal Proteostasismentioning

confidence: 99%

Global and local mechanisms sustain axonal proteostasis of transmembrane proteins

Cornejo

Luarte

Couve

2017

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“…To further our understanding of EphB2 trans‐endocytosis we next sought to identify novel components of the endocytic complex. Studies using immuno‐precipitation and mass spectrometry methods to map the interactome of EphB2 have not yielded data that identify endocytic proteins . We therefore decided to target our search to the previously identified endocytic adaptor protein of EphB2, Numb .…”

Section: Resultsmentioning

confidence: 99%

“…In order to understand how the EphB‐ephrinB complex is trans‐endocytosed, identification of novel interactions with endocytic proteins that are bound to the complex is necessary, as this is a poorly defined mechanism. Studies using proteomics approaches to identify novel interaction partners of the EphB2 receptor have not yet identified proteins involved in receptor trafficking . In this study we therefore instead used a targeted approach and employed the EphB2 interaction partner Numb as a starting point to show that it directly interacted with endocytic proteins Eps15 and Eps15R.…”

Section: Discussionmentioning

confidence: 99%

Eps15R and clathrin regulate EphB2‐mediated cell repulsion

Evergren

Cobbe

McMahon

2017

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Expression of Eph receptors and their ligands, the ephrins, have important functions in boundary formation and morphogenesis in both adult and embryonic tissue. The EphB receptors and ephrinB ligands are transmembrane proteins that are expressed in different cells and their interaction drives cell repulsion. For cell repulsion to occur, trans‐endocytosis of the inter‐cellular receptor‐ligand EphB‐ephrinB complex is required. The molecular mechanism underlying trans‐endocytosis is poorly defined. Here we show that the process is clathrin‐ and Eps15R‐mediated using Co115 colorectal cell lines stably expressing EphB2 and ephrinB1. Cell repulsion in co‐cultures of EphB2‐ and ephrinB1‐expressing cells is significantly reduced by knockdown of Eps15R but not Eps15. A novel interaction motif in Eps15R, DPFxxLDPF, is shown to bind directly to the clathrin terminal domain in vitro. Moreover, the interaction between Eps15R and clathrin is required for EphB2‐mediated cell repulsion as shown in a rescue experiment in the EphB2 co‐culture assay where wild type Eps15R but not the clathrin‐binding mutant rescues cell repulsion. These results provide the first evidence that Eps15R together with clathrin control EphB/ephrinB trans‐endocytosis and thereby cell repulsion.

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“…In the central nervous system, exosomes secreted by oligodendrocytes have been associated with enhanced neuronal viability and an increase in neuron firing rate [111,112]. Less is known about the role of EVs in neuron-neuron communication, although recently neuronal EVs carrying Ephrin B2 have been shown to induce growth cone collapse, a critical component of axon pathfinding [113]. Together, these studies suggest that an important role of EVs in the nervous system is to promote structural remodeling in a diverse set of circumstances.…”

Section: Physiological Roles Of Evsmentioning

confidence: 99%

Extracellular Vesicles: Unique Intercellular Delivery Vehicles

Maas

Breakefield

Weaver

2017

Trends in Cell Biology

1,118

969

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Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound carriers with complex cargos, including proteins, lipids and nucleic acids. While release of EVs was previously thought to be only a mechanism to discard nonfunctional cellular components, increasing evidence implicates EVs as key players in intercellular and even interorganismal communication. EVs confer stability and can direct their cargoes to specific cell types. EV cargoes also appear to act in a combinatorial manner to communicate directives to other cells. This review will focus on recent findings and knowledge gaps in the area of EV biogenesis, release, and uptake. In addition, we highlight examples whereby EV cargoes control basic cellular functions, including motility and polarization, immune responses, and development, as well as contribute to diseases, such as cancer and neurodegeneration.

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

Abstract: Ephs interact with ESCRT complex components and are released via extracellular vesicles or exosomes. EphB2 released via exosomes mediates a novel cell contact–independent mode of ephrin-Eph signaling that contributes to axon guidance in cell–cell repulsion processes.

Cited by 111 publications

References 43 publications

Global and local mechanisms sustain axonal proteostasis of transmembrane proteins

Global and local mechanisms sustain axonal proteostasis of transmembrane proteins

Eps15R and clathrin regulate EphB2‐mediated cell repulsion

Extracellular Vesicles: Unique Intercellular Delivery Vehicles

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