Sci. Signal., 18 March 2008
Cell Migration Keeping Things Moving
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
The Rho guanosine triphosphatase (GTPase) family member Cdc42 is critical for cell migration. Cdc42 mediates the formation of membrane protrusions such as lamellipodia at the leading edge, and it participates in the polarization of centrosomes in migrating cells. Cdc42 is activated through the binding of GTP, which is facilitated by guanine nucleotide exchange factors. The GTPase-activating protein (GAP) Cdc42GAP catalyzes the hydrolysis of GTP, thus inhibiting Cdc42 activity. However, exactly how Cdc42GAP is regulated to ensure the appropriate abundance of active Cdc42 at the cells leading edge is unclear. Shen et al. investigated a role for Nudel, a protein that regulates the motor protein dynein, in the regulation of Cdc42GAP. Microscopic analysis showed that NIH 3T3 cells transfected with Nudel-specific RNA interference (RNAi) formed fewer protrusions, migrated less efficiently, and had less polarized localization of centrosomes compared with control cells. Nudel was recruited to the leading edge of migrating cells, where it colocalized with Cdc42GAP. Coimmunoprecipitation experiments confirmed this interaction and showed that Cdc42GAP interacted with either Nudel or Cdc42 but not with both at the same time. Pull-down assays demonstrated that Nudel competed with Cdc42 for binding to Cdc42GAP in a dose-dependent manner. A fluorescence-based assay showed that Cdc42 activation was lower in NIH 3T3 cells transfected with Nudel-specific RNAi than in control cells. Western blotting and microscopic analyses demonstrated that recruitment of Nudel to the leading edge was dependent on its phosphorylation by extracellular signal-regulated kinases. Together these data suggest a critical role for Nudel in cell migration through its binding to the Cdc42 inhibitor Cdc42GAP, thus allowing for increased Cdc42 activity.
Y. Shen, N. Li, S. Wu, Y. Zhou, Y. Shan, Q. Zhang, C. Ding, Q. Yuan, F. Zhao, R. Zeng, X. Zhu, Nudel binds Cdc42GAP to modulate Cdc42 activity at the leading edge of migrating cells. Dev. Cell 14, 342-353 (2008). [PubMed]
Citation: J. F. Foley, Keeping Things Moving. Sci. Signal. 1, ec102 (2008).
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