Recruitment of Eph receptors into signaling clusters does not require ephrin contact

Wimmer-Kleikamp, Sabine; Janes, Peter W.; Squire, Anthony; Bastiaens, Philippe I. H.; Lackmann, Martin

doi:10.1083/jcb.200312001

Cited by 120 publications

(124 citation statements)

References 27 publications

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“…5A). Importantly, ligand-independent activation of the ΔCRD mutant was most strongly affected, confirming its critical role in Eph signaling initiation as was suggested previously for EphA3 (3,5).…”

Section: Role Of the Eph/eph Interfaces For Stability And Function Ofsupporting

confidence: 85%

“…We confirmed this concept by structure-based mutagenesis in combination with cell-based signaling and receptor-visualization assays, also explaining the previously observed recruitment of non-ligandbound receptors into signaling clusters (5). The presence at the cell surface of highly ordered receptor assemblies is a unique feature of the Eph receptors and has not been observed in any other receptor kinase family.…”

Section: Implications For Eph Signaling Initiationsupporting

confidence: 84%

“…Our study reveals the structure of the functional Eph/ephrin assemblies at the cell surface and suggests a mechanism for Eph receptor clustering and activation that involves bivalent homotypic interactions between the LBD and CRD domains in neighboring receptors. Previously, we demonstrated that the CRD plays a critical role in the formation of Eph/ephrin "signalosomes" (3,5) and now reveal the specific molecular regions involved, as well as the underlying structural mechanisms. Focusing on EphA2, we determined a series of EphA2 ectodomain structures containing the CRD, including that of the full EphA2 extracellular region, both alone and in complex with A-class ephrin ligands.…”

Section: Implications For Eph Signaling Initiationmentioning

confidence: 85%

“…Furthermore, earlier findings indicated that Eph-Eph interactions via a C-terminal ectodomain region outside the LBD are critical for Eph function during development (3). Presumably such Eph-Eph interfaces act to recruit non-ligand-bound Eph receptors into Eph clusters (5). In addition, a random mutagenesis survey of the EphA3 ectodomain revealed that binding to ephrinA5 requires an interaction site located in the CRD.…”

mentioning

confidence: 99%

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Architecture of Eph receptor clusters

Himanen

Yermekbayeva

Janes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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229

304

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Eph receptor tyrosine kinases and their ephrin ligands regulate cell navigation during normal and oncogenic development. Signaling of Ephs is initiated in a multistep process leading to the assembly of higher-order signaling clusters that set off bidirectional signaling in interacting cells. However, the structural and mechanistic details of this assembly remained undefined. Here we present high-resolution structures of the complete EphA2 ectodomain and complexes with ephrin-A1 and A5 as the base unit of an Eph cluster. The structures reveal an elongated architecture with novel Eph/Eph interactions, both within and outside of the Eph ligand-binding domain, that suggest the molecular mechanism underlying Eph/ephrin clustering. Structure-function analysis, by using site-directed mutagenesis and cell-based signaling assays, confirms the importance of the identified oligomerization interfaces for Eph clustering.cell-cell attraction and repulsion | Eph receptor clustering

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Section: Role Of the Eph/eph Interfaces For Stability And Function Ofsupporting

confidence: 85%

Section: Implications For Eph Signaling Initiationsupporting

confidence: 84%

Section: Implications For Eph Signaling Initiationmentioning

confidence: 85%

mentioning

confidence: 99%

See 2 more Smart Citations

Architecture of Eph receptor clusters

Himanen

Yermekbayeva

Janes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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229

304

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“…Ephrin-A5 forward signaling to EphA receptors is me-diated by tetrameric or higher order cell surface EphA clustering (25,26). This is blocked by the EphA5-Fc construct (27)(28)(29)(30), as shown in the previous in vitro and in vivo studies.…”

Section: Resultsmentioning

confidence: 81%

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

Overman¹,

Clarkson

Wanner³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

227

310

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Stroke causes loss of neurological function. Recovery after stroke is facilitated by forced use of the affected limb and is associated with sprouting of new connections, a process that is sharply confined in the adult brain. We show that ephrin-A5 is induced in reactive astrocytes in periinfarct cortex and is an inhibitor of axonal sprouting and motor recovery in stroke. Blockade of ephrin-A5 signaling using a unique tissue delivery system induces the formation of a new pattern of axonal projections in motor, premotor, and prefrontal circuits and mediates recovery after stroke in the mouse through these new projections. Combined blockade of ephrin-A5 and forced use of the affected limb promote new and surprisingly widespread axonal projections within the entire cortical hemisphere ipsilateral to the stroke. These data indicate that stroke activates a newly described membrane-bound astrocyte growth inhibitor to limit neuroplasticity, activity-dependent axonal sprouting, and recovery in the adult.cortical map | regeneration | repair | motor function | EphA4

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Nonisothermal crystallization kinetics of linear metallocene polyethylenes

Hussein

2007

J of Applied Polymer Sci

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The effect of weight-average molecular weight (M w ) on the nonisothermal crystallization kinetics of linear metallocene polyethylene (m-PE) was studied with modulated differential scanning calorimetry. Six linear mPEs of molecular weights in the range 122-934 kg/mol were prepared by gas-phase polymerization. The cooling rate (R) was varied in the range 2-208C/min, and it significantly affected the crystallization behavior. M w had a weak influence on both the peak crystallization temperature and the crystallization onset temperature. All m-PEs showed primary and secondary crystallizations. At both low and high R's, the crystallinity showed a significant drop ($ 30%) when M w was increased from 122 to 934 kg/mol. At low R's (< 108C/min), the rate parameters in the modified Avrami method [primary rate constant (k R )] and Mo method [F(T)] of analyses agreed in suggesting that an increased M w slowed the rate of crystallization. The M w dependency of k R followed the Arrhenius type (k R 5 k Ro e 281 /M w , where k Ro is a rate-dependent constant). However, at higher R's, k R approached a constant value. The order parameters obtained by the different methods of analysis (n and a) were independent of M w , which suggests that the crystal type remained the same. Hoffman-Lauritzen theory was used for data analysis, and activation energy per segment showed a significant decrease, from 225.0 to 11.8 kJ/mol, when M w was increased from 152 to 934 kg/mol. Finally, all methods of analysis suggested a significant effect of M w on slowing the overall crystallization process.

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Recruitment of Eph receptors into signaling clusters does not require ephrin contact

Cited by 120 publications

References 27 publications

Architecture of Eph receptor clusters

Architecture of Eph receptor clusters

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

Nonisothermal crystallization kinetics of linear metallocene polyethylenes

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