Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse.
Ephs regulate growth cone repulsion, a process controlled by the actin cytoskeleton. The guanine nucleotide exchange factor (GEF) ephexin1 interacts with EphA4 and has been suggested to mediate the effect of EphA on the activity of Rho GTPases, key regulators of the cytoskeleton and axon guidance. Using cultured ephexin1-/- mouse neurons and RNA interference in the chick, we report that ephexin1 is required for normal axon outgrowth and ephrin-dependent axon repulsion. Ephexin1 becomes tyrosine phosphorylated in response to EphA signaling in neurons, and this phosphorylation event is required for growth cone collapse. Tyrosine phosphorylation of ephexin1 enhances ephexin1's GEF activity toward RhoA while not altering its activity toward Rac1 or Cdc42, thus changing the balance of GTPase activities. These findings reveal that ephexin1 plays a role in axon guidance and is regulated by a switch mechanism that is specifically tailored to control Eph-mediated growth cone collapse.
Sahin
Mustafa
M
Neurobiology Program, Children's Hospital, Boston, Massachusetts 02115, USA.
Greer
Paul L
PL
Lin
Michael Z
MZ
Poucher
Heather
H
Eberhart
Johann
J
Schmidt
Susanne
S
Wright
Tracy M
TM
Shamah
Steven M
SM
O'connell
Sinead
S
Cowan
Christopher W
CW
Hu
Linda
L
Goldberg
Jeffrey L
JL
Debant
Anne
A
Corfas
Gabriel
G
Krull
Catherine E
CE
Greenberg
Michael E
ME
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002642:Chick Embryo; D003599:Cytoskeleton / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D010766:Phosphorylation; D036082:Receptor, EphA1 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; C504479:Ngef protein, mouse; D014443:Tyrosine; D036082:Receptor, EphA1; D020741:rho GTP-Binding Proteins