Regulation of EphA 4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function.
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.
Egea
Joaquim
J
Max-Planck Institute of Neurobiology, 82152 Martinsried, Germany.
Nissen
Ulla Vig
UV
Dufour
Audrey
A
Sahin
Mustafa
M
Greer
Paul
P
Kullander
Klas
K
Mrsic-Flogel
Thomas D
TD
Greenberg
Michael E
ME
Kiehn
Ole
O
Vanderhaeghen
Pierre
P
Klein
Rüdiger
R
D000818:Animals; D000831:Animals, Newborn; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000254:growth & development* / Q000378:metabolism; D036342:Ephrins / Q000378:metabolism*; D020439:Growth Cones / Q000378:metabolism* / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D009415:Nerve Net / Q000254:growth & development / Q000378:metabolism; D009434:Neural Pathways / Q000254:growth & development* / Q000378:metabolism; D010766:Phosphorylation; D011940:Receptor Aggregation / Q000502:physiology*; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*; D036081:Receptors, Eph Family / Q000378:metabolism; D013116:Spinal Cord / Q000254:growth & development / Q000378:metabolism
D036342:Ephrins; D020662:Guanine Nucleotide Exchange Factors; C504481:NGEF protein, human; C504479:Ngef protein, mouse; D036122:Receptor, EphA4; D036081:Receptors, Eph Family