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MBC in Press, published online ahead of print January 4, 2006
Mol. Biol. Cell 10.1091/mbc.E05-03-0237

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Submitted on March 21, 2005
Revised on December 18, 2005
Accepted on December 28, 2005

Deregulation of HEF1 Impairs M-Phase Progression by Disrupting the RhoA Activation Cycle

Disha Dadke, Michael Jarnik, Elena N. Pugacheva, Mahendra K. Singh, and Erica A. Golemis

Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111

Monitoring Editor: Jean Schwarzbauer

The focal adhesion-associated signaling protein HEF1 undergoes a striking relocalization to the spindle at mitosis, but a function for HEF1 in mitotic signaling has not been demonstrated. We here report that overexpression of HEF1 leads to failure of cells to progress through cytokinesis, while depletion of HEF1 by siRNA leads to defects earlier in M-phase before cleavage furrow formation. These defects can be explained mechanistically by our determination that HEF1 regulates the activation cycle of RhoA. Inactivation of RhoA has long been known to be required for cytokinesis, while it has recently been determined that activation of RhoA at the entry to M-phase is required for cellular rounding. We find that increased HEF1 sustains RhoA activation, whereas depleted HEF1 reduces RhoA activation. Further, we demonstrate that chemical inhibition of RhoA is sufficient to reverse HEF1-dependent cellular arrest at cytokinesis. Finally, we demonstrate that HEF1 associates with the RhoA-GTP exchange factor ECT2, an ortholog of the Drosophila cytokinetic regulator Pebble, providing a direct means for HEF1 control of RhoA. We conclude that HEF1 is a novel component of the cell division control machinery, and that HEF1 activity impacts division as well as cell attachment signaling events.

Address correspondence to: Erica A. Golemis (EA_Golemis{at}fccc.edu)




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