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PMID:18331715

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Citation

Shen, Y, Li, N, Wu, S, Zhou, Y, Shan, Y, Zhang, Q, Ding, C, Yuan, Q, Zhao, F, Zeng, R and Zhu, X (2008) Nudel binds Cdc42GAP to modulate Cdc42 activity at the leading edge of migrating cells. Dev. Cell 14:342-53

Abstract

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.

Links

PubMed Online version:10.1016/j.devcel.2008.01.001

Keywords

Animals; Carrier Proteins/antagonists & inhibitors; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line; Cell Movement/physiology; Cell Polarity; Centrosome/metabolism; Dyneins/metabolism; GTPase-Activating Proteins/genetics; GTPase-Activating Proteins/metabolism; Humans; Mice; Models, Biological; Mutation; NIH 3T3 Cells; Phosphorylation; Protein Binding; RNA Interference; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; cdc42 GTP-Binding Protein/genetics; cdc42 GTP-Binding Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DCTN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9ERR1

F

Seeded From UniProt

complete

MOUSE:DCTN1

located_in

GO:0031252: cell leading edge

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:1433E

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9ERR1

F

Seeded From UniProt

complete

MOUSE:LIS1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9ERR1

F

Seeded From UniProt

complete

MOUSE:RHG01

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9ERR1

F

Seeded From UniProt

complete

MOUSE:RHG01

located_in

GO:0031252: cell leading edge

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NDEL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q5FWK3

F

Seeded From UniProt

complete

MOUSE:NDEL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P62259

F

Seeded From UniProt

complete

MOUSE:NDEL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O08788

F

Seeded From UniProt

complete

MOUSE:NDEL1

acts_upstream_of_or_within

GO:0016477: cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NDEL1

enables

GO:0043014: alpha-tubulin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NDEL1

located_in

GO:0031252: cell leading edge

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NDEL1

enables

GO:0048487: beta-tubulin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NDEL1

acts_upstream_of_or_within

GO:0051642: centrosome localization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NDEL1

acts_upstream_of_or_within

GO:0090630: activation of GTPase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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