Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway.
The Slit protein guides neuronal and leukocyte migration through the transmembrane receptor Roundabout (Robo). We report here that the intracellular domain of Robo interacts with a novel family of Rho GTPase activating proteins (GAPs). Two of the Slit-Robo GAPs (srGAPs) are expressed in regions responsive to Slit. Slit increased srGAP1-Robo1 interaction and inactivated Cdc42. A dominant negative srGAP1 blocked Slit inactivation of Cdc42 and Slit repulsion of migratory cells from the anterior subventricular zone (SVZa) of the forebrain. A constitutively active Cdc42 blocked the repulsive effect of Slit. These results have demonstrated important roles for GAPs and Cdc42 in neuronal migration. We propose a signal transduction pathway from the extracellular guidance cue to intracellular actin polymerization.
Wong
K
K
Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110, USA.
Ren
X R
XR
Huang
Y Z
YZ
Xie
Y
Y
Liu
G
G
Saito
H
H
Tang
H
H
Wen
L
L
Brady-Kalnay
S M
SM
Mei
L
L
Wu
J Y
JY
Xiong
W C
WC
Rao
Y
Y
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D015152:Blotting, Northern; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D029721:Drosophila Proteins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D005799:Genes, Dominant; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D020798:Two-Hybrid System Techniques; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D000097905:Roundabout Proteins
D000199:Actins; D029721:Drosophila Proteins; D020558:GTP Phosphohydrolases; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D020764:cdc42 GTP-Binding Protein; D000097905:Roundabout Proteins; C066819:sli protein, Drosophila