Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function

Joaquim Egea; Ulla Vig Nissen; Audrey Dufour; Mustafa Sahin; Paul Greer; Klas Kullander; Thomas D. Mrsic-Flogel; Michael E. Greenberg; Ole Kiehn; Pierre Vanderhaeghen; Rüdiger Klein

doi:10.1016/j.neuron.2005.06.029

Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function

Joaquim Egea, Ulla Vig Nissen, Audrey Dufour, Mustafa Sahin, Paul Greer, Klas Kullander, Thomas D. Mrsic-Flogel, Michael E. Greenberg, Ole Kiehn, Pierre Vanderhaeghen, Rüdiger Klein^*

^*Corresponding author af dette arbejde

92 Citationer (Scopus)

Abstract

Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also requires clustering by their membrane bound ephrin ligands. The relative importance of Eph kinase activity and clustering for in vivo functions is unknown. We find that knockin mice expressing a mutant form of EphA4 (EphA4 ^EE), whose kinase is constitutively activated in the absence of ephrinB ligands, are deficient in the development of thalamocortical projections and some aspects of central pattern generator rhythmicity. Surprisingly, other functions of EphA4 were regulated normally by EphA4^EE, including midline axon guidance, hindlimb locomotion, in vitro growth cone collapse, and phosphorylation of ephexin1. These results suggest that signaling of Eph RTKs follows a multistep process of induced kinase activity and higher-order clustering different from RTKs responding to soluble ligands.

Originalsprog	Engelsk
Tidsskrift	Neuron
Vol/bind	47
Udgave nummer	4
Sider (fra-til)	515-528
Antal sider	14
ISSN	0896-6273
DOI	https://doi.org/10.1016/j.neuron.2005.06.029
Status	Udgivet - 18 aug. 2005

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Egea, J., Nissen, U. V., Dufour, A., Sahin, M., Greer, P., Kullander, K., Mrsic-Flogel, T. D., Greenberg, M. E., Kiehn, O., Vanderhaeghen, P., & Klein, R. (2005). Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function. Neuron, 47(4), 515-528. https://doi.org/10.1016/j.neuron.2005.06.029

Egea, J, Nissen, UV, Dufour, A, Sahin, M, Greer, P, Kullander, K, Mrsic-Flogel, TD, Greenberg, ME, Kiehn, O, Vanderhaeghen, P & Klein, R 2005, 'Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function', Neuron, bind 47, nr. 4, s. 515-528. https://doi.org/10.1016/j.neuron.2005.06.029

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title = "Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function",

abstract = "Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also requires clustering by their membrane bound ephrin ligands. The relative importance of Eph kinase activity and clustering for in vivo functions is unknown. We find that knockin mice expressing a mutant form of EphA4 (EphA4 EE), whose kinase is constitutively activated in the absence of ephrinB ligands, are deficient in the development of thalamocortical projections and some aspects of central pattern generator rhythmicity. Surprisingly, other functions of EphA4 were regulated normally by EphA4EE, including midline axon guidance, hindlimb locomotion, in vitro growth cone collapse, and phosphorylation of ephexin1. These results suggest that signaling of Eph RTKs follows a multistep process of induced kinase activity and higher-order clustering different from RTKs responding to soluble ligands.",

author = "Joaquim Egea and Nissen, {Ulla Vig} and Audrey Dufour and Mustafa Sahin and Paul Greer and Klas Kullander and Mrsic-Flogel, {Thomas D.} and Greenberg, {Michael E.} and Ole Kiehn and Pierre Vanderhaeghen and R{\"u}diger Klein",

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doi = "10.1016/j.neuron.2005.06.029",

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T1 - Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function

AU - Egea, Joaquim

AU - Nissen, Ulla Vig

AU - Dufour, Audrey

AU - Sahin, Mustafa

AU - Greer, Paul

AU - Kullander, Klas

AU - Mrsic-Flogel, Thomas D.

AU - Greenberg, Michael E.

AU - Kiehn, Ole

AU - Vanderhaeghen, Pierre

AU - Klein, Rüdiger

PY - 2005/8/18

Y1 - 2005/8/18

N2 - Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also requires clustering by their membrane bound ephrin ligands. The relative importance of Eph kinase activity and clustering for in vivo functions is unknown. We find that knockin mice expressing a mutant form of EphA4 (EphA4 EE), whose kinase is constitutively activated in the absence of ephrinB ligands, are deficient in the development of thalamocortical projections and some aspects of central pattern generator rhythmicity. Surprisingly, other functions of EphA4 were regulated normally by EphA4EE, including midline axon guidance, hindlimb locomotion, in vitro growth cone collapse, and phosphorylation of ephexin1. These results suggest that signaling of Eph RTKs follows a multistep process of induced kinase activity and higher-order clustering different from RTKs responding to soluble ligands.

AB - Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also requires clustering by their membrane bound ephrin ligands. The relative importance of Eph kinase activity and clustering for in vivo functions is unknown. We find that knockin mice expressing a mutant form of EphA4 (EphA4 EE), whose kinase is constitutively activated in the absence of ephrinB ligands, are deficient in the development of thalamocortical projections and some aspects of central pattern generator rhythmicity. Surprisingly, other functions of EphA4 were regulated normally by EphA4EE, including midline axon guidance, hindlimb locomotion, in vitro growth cone collapse, and phosphorylation of ephexin1. These results suggest that signaling of Eph RTKs follows a multistep process of induced kinase activity and higher-order clustering different from RTKs responding to soluble ligands.

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U2 - 10.1016/j.neuron.2005.06.029

DO - 10.1016/j.neuron.2005.06.029

M3 - Journal article

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SN - 0896-6273

VL - 47

SP - 515

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JO - Neuron

JF - Neuron

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Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function

Abstract

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