Deregulation of HEF1 impairs M-phase progression by disrupting the RhoA activation cycle

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

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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, whereas depletion of HEF1 by small interfering RNA (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, whereas 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 by siRNA reduces RhoA activation. Furthermore, 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 orthologue 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.

Original languageEnglish (US)
Pages (from-to)1204-1217
Number of pages14
JournalMolecular Biology of the Cell
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2006
Externally publishedYes

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Cytokinesis
Cell Division
Small Interfering RNA
Focal Adhesions
Guanosine Triphosphate
Mitosis
Drosophila
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Deregulation of HEF1 impairs M-phase progression by disrupting the RhoA activation cycle. / Dadke, Disha; Jarnik, Michael; Pugacheva, Elena N.; Singh, Mahendra; Golemis, Erica A.

In: Molecular Biology of the Cell, Vol. 17, No. 3, 01.03.2006, p. 1204-1217.

Research output: Contribution to journalArticle

Dadke, Disha ; Jarnik, Michael ; Pugacheva, Elena N. ; Singh, Mahendra ; Golemis, Erica A. / Deregulation of HEF1 impairs M-phase progression by disrupting the RhoA activation cycle. In: Molecular Biology of the Cell. 2006 ; Vol. 17, No. 3. pp. 1204-1217.
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