p130CAS is required for netrin signaling and commissural axon guidance.
Netrins are an important family of axon guidance cues. Here, we report that netrin-1 induces tyrosine phosphorylation of p130(CAS) (Crk-associated substrate). Our biochemical studies indicate that p130(CAS) is downstream of the Src family kinases and upstream of the small GTPase Rac1 and Cdc42. Inhibition of p130(CAS) signaling blocks both the neurite outgrowth-promoting activity and the axon attraction activity of netrin-1. p130(CAS) RNA interference inhibits the attraction of commissural axons in the spinal cord by netrin-1 and causes defects in commissural axon projection in the embryo. These results demonstrate that p130(CAS) is a key component in the netrin signal transduction pathway and plays an important role in guiding commissural axons in vivo.
Liu
Guofa
G
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Li
Weiquan
W
Gao
Xue
X
Li
Xiaoling
X
Jürgensen
Claudia
C
Park
Hwan-Tae
HT
Shin
Nah-Young
NY
Yu
Jian
J
He
Ming-Liang
ML
Hanks
Steven K
SK
Wu
Jane Y
JY
Guan
Kun-Liang
KL
Rao
Yi
Y
D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002642:Chick Embryo; D050719:Crk-Associated Substrate Protein / Q000502:physiology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009414:Nerve Growth Factors / Q000502:physiology*; D000075388:Netrin-1; D011247:Pregnancy; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology
D050719:Crk-Associated Substrate Protein; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D020830:rac1 GTP-Binding Protein