Nudel binds Cdc42GAP to modulate Cdc42 activity at the leading edge of migrating cells.
Cdc42GAP promotes inactivation of Cdc42, a small GTPase whose activation at the leading edge by guanine nucleotide exchange factors is critical for cell migration. How Cdc42GAP is regulated to ensure proper levels of active Cdc42 is poorly understood. Here we show that Nudel, a cytoplasmic dynein regulator, competes with Cdc42 for binding Cdc42GAP. Consequently, Nudel can inhibit Cdc42GAP-mediated inactivation of Cdc42 in a dose-dependent manner. Both Nudel and Cdc42GAP exhibit leading-edge localization in migrating cells. The localization of Nudel requires its phosphorylation by Erk1/2. Depleting Nudel by RNAi or overexpression of a nonphosphorylatable mutant abolishes Cdc42 activation and cell migration. Our data thus uncover Nudel as a regulator of Cdc42 during cell migration. Nudel facilitates cell migration by sequestering Cdc42GAP at the leading edge to stabilize active Cdc42 in response to extracellular stimuli. Excess active Cdc42 may in turn control its own activity by recruiting Cdc42GAP from Nudel.
Shen
Yidong
Y
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
Li
Ning
N
Wu
Shuang
S
Zhou
Yizhuo
Y
Shan
Yongli
Y
Zhang
Qiangge
Q
Ding
Chong
C
Yuan
Quan
Q
Zhao
Fukun
F
Zeng
Rong
R
Zhu
Xueliang
X
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity; D018385:Centrosome / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C505158:Arhgap1 protein, mouse; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; C421108:NDEL1 protein, human; C486015:Ndel1 protein, mouse; D011993:Recombinant Fusion Proteins; D004398:Dyneins; D020764:cdc42 GTP-Binding Protein