EphA receptor tyrosine kinases interact with co-expressed ephrin-A ligands in cis

Yin, Yanzhi; Yamashita, Yukie; Noda, Hirono; Okafuji, Tatsuya; Go, Masahiro J.; Tanaka, Hideaki

doi:10.1016/j.neures.2003.11.009

Cited by 90 publications

(80 citation statements)

References 27 publications

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“…This could reflect homotypic cellular interactions operating under these conditions (e.g., cell contacts involving extended axons) or, alternatively, cell autonomous functions of these cell adhesion molecules. For example, cis interactions have been observed between ephrin ligands and Eph receptors as well as between N-cadherin monomers (Takeda et al, 1999;Shan et al, 2000;Yin et al, 2004;Marquardt et al, 2005) (see also below).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Factor I Coordinates Multiple Phases of Cerebellar Granule Cell Development via Regulation of Cell Adhesion Molecules

Wang¹,

Mullikin‐Kilpatrick²,

Crandall³

et al. 2007

Journal of Neuroscience

149

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A central question is how various stages of neuronal development are integrated as a differentiation program. Here we show that the nuclear factor I (NFI) family of transcriptional regulators is expressed and functions throughout the postmitotic development of cerebellar granule neurons (CGNs). Expression of an NFI dominant repressor in CGN cultures blocked axon outgrowth and dendrite formation and decreased CGN migration. Inhibition of NFI transactivation also disrupted extension and fasciculation of parallel fibers as well as CGN migration to the internal granule cell layer in cerebellar slices. In postnatal day 17 Nfia-deficient mice, parallel fibers were greatly diminished and disoriented, CGN dendrite formation was dramatically impaired, and migration from the external germinal layer (EGL) was retarded. Axonal marker expression also was disrupted within the EGL of embryonic day 18 Nfib-null mice. NFI regulation of axon extension was observed under conditions of homotypic cell contact, implicating cell surface proteins as downstream mediators of its actions in CGNs. Consistent with this, the cell adhesion molecules ephrin B1 and N-cadherin were identified as NFI gene targets in CGNs using inhibitor and Nfi mutant analysis as well as chromatin immunoprecipitation. Functional inhibition of ephrin B1 or N-cadherin interfered with CGN axon extension and guidance, migration, and dendritogenesis in cell culture as well as in situ. These studies define NFI as a key regulator of postmitotic CGN development, in particular of axon formation, dendritogenesis, and migratory behavior. Furthermore, they reveal how a single transcription factor family can control and integrate multiple aspects of neuronal differentiation through the regulation of cell adhesion molecules.

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Section: Discussionmentioning

confidence: 99%

Nuclear Factor I Coordinates Multiple Phases of Cerebellar Granule Cell Development via Regulation of Cell Adhesion Molecules

Wang¹,

Mullikin‐Kilpatrick²,

Crandall³

et al. 2007

Journal of Neuroscience

149

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“…Surprisingly though, different Eph receptors and ephrins are often co-expressed by the same cells raising the question about potential interactions in cis (within the same cell) affecting the functional signaling in trans (between the opposing cells). The in-cis-interaction theory gained momentum after several reports indicated that the responsiveness of EphA expressing retinal axons is negatively modulated by A-class ligands expressed on the same cells [43,44]. Interestingly, a seemingly contradictory conclusion was published by Marquardt, Pfaff and colleagues [45], who documented that at least in spinal motor neurons coexpressed Ephs and ephrins segregate laterally into distinct membrane domains from which they induce opposing effects: EphAs direct growth cone collapse/repulsion, while ephrin-As signal motor axon growth/attraction.…”

Section: Eph/ephrin Interactions On the Surface Of The Same Cellmentioning

confidence: 99%

“…In a recent study [46**], the hypothesis of functional Eph/ephrin interactions within the same membrane was revitalized, identifying two types of of Eph/ephrin interactions in cis: (i) "masking" interactions involving the ligand binding domain of the receptor [44], and (ii) novel inhibitory interactions (abolishing EphA activation) involving other receptor domains. Importantly the authors suggest that the formation of in-cis complexes transforms the uniform expression of EphAs in the nasal part of the retina into a gradient of functional EphAs and has a key role in controlling retinotectal mapping [46**, 47].…”

Section: Eph/ephrin Interactions On the Surface Of The Same Cellmentioning

confidence: 99%

Cell–cell signaling via Eph receptors and ephrins

Himanen

Saha

Nikolov

2007

Current Opinion in Cell Biology

225

202

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SummaryEph receptors are the largest subfamily of receptor tyrosine kinases regulating cell shape, movements and attachment. The interactions of the Ephs with their ephrin ligands are restricted to the sites of cell-cell contact since both molecules are membrane attached. This review summarizes recent advances in our understanding of the molecular mechanisms underlining the diverse functions of the molecules during development and in the adult organism. The unique properties of this signaling system that are of highest interest and have been the focus of intense investigations are as follows: (i) the signal is often simultaneously transduced in both ligand-and receptor-expressing cells, (ii) signaling via the same molecules can generate opposing cellular reactions depending on the context, and (iii) the Ephs and the ephrins are divided in two subclasses with promiscuous intra-subclass interactions, but rarely observed inter-subclass interactions.

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“…Co-expression of different Eph/EFN members is commonly observed and some of them have been referred as a mechanism of regulation of Eph/EFNs signaling. These include receptor-ligand interactions in cis [32][33][34] and the formation of Eph receptor heterocomplexes, including the participation of kinase-defective Eph receptors like EphB6 and/or splice variants, 16 which modulates the magnitude and type of signaling and the cell outcome. Thus, it would be interesting to carry out adhesion and TEM assays by co-culturing mixtures of EphA2-Fc treated and non-treated B cells as well as different combinations of B-cell subpopulations according to other differentially co-expressed members.…”

Section: Contextualizing Epha2-efna4 Interactions As Possible Guidingmentioning

confidence: 99%

Eph-ephrin bidirectional signaling comes into the context of lymphocyte transendothelial migration

Trinidad

Zapata

Alonso-Colmenar

2010

Cell Adhesion & Migration

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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 endotheliumlymphocyte 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.

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EphA receptor tyrosine kinases interact with co-expressed ephrin-A ligands in cis

Cited by 90 publications

References 27 publications

Nuclear Factor I Coordinates Multiple Phases of Cerebellar Granule Cell Development via Regulation of Cell Adhesion Molecules

Nuclear Factor I Coordinates Multiple Phases of Cerebellar Granule Cell Development via Regulation of Cell Adhesion Molecules

Cell–cell signaling via Eph receptors and ephrins

Eph-ephrin bidirectional signaling comes into the context of lymphocyte transendothelial migration

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