Leukemia-associated RhoGEF (LARG) is a novel RhoGEF in cytokinesis and required for the proper completion of abscission.

Authors

Matthew K Martz, Department of Biochemistry and Molecular Biology, Thomas Jefferson UniversityFollow
Elda Grabocka, Department of Biochemistry and Molecular Biology, Thomas Jefferson University; Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical CenterFollow
Neil Beeharry, Fox Chase Cancer Center
Timothy J Yen, Fox Chase Cancer Center
Philip B Wedegaertner, Department of Biochemistry and Molecular Biology, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

9-15-2013

Comments

This article has been peer reviewed and is published in Molecular Biology of the Cell

The published version is available at DOI: 10.1091/mbc.E12-07-0533

© 2013 Martz et al.

Abstract

Proper completion of mitosis requires the concerted effort of multiple RhoGEFs. Here we show that leukemia-associated RhoGEF (LARG), a RhoA-specific RGS-RhoGEF, is required for abscission, the final stage of cytokinesis, in which the intercellular membrane is cleaved between daughter cells. LARG colocalizes with α-tubulin at the spindle poles before localizing to the central spindle. During cytokinesis, LARG is condensed in the midbody, where it colocalizes with RhoA. HeLa cells depleted of LARG display apoptosis during cytokinesis with unresolved intercellular bridges, and rescue experiments show that expression of small interfering RNA-resistant LARG prevents this apoptosis. Moreover, live cell imaging of LARG-depleted cells reveals greatly delayed fission kinetics in abscission in which a population of cells with persistent bridges undergoes apoptosis; however, the delayed fission kinetics is rescued by Aurora-B inhibition. The formation of a Flemming body and thinning of microtubules in the intercellular bridge of cells depleted of LARG is consistent with a defect in late cytokinesis, just before the abscission event. In contrast to studies of other RhoGEFs, particularly Ect2 and GEF-H1, LARG depletion does not result in cytokinetic furrow regression nor does it affect internal mitotic timing. These results show that LARG is a novel and temporally distinct RhoGEF required for completion of abscission.

Recommended Citation

Martz, Matthew K; Grabocka, Elda; Beeharry, Neil; Yen, Timothy J; and Wedegaertner, Philip B, "Leukemia-associated RhoGEF (LARG) is a novel RhoGEF in cytokinesis and required for the proper completion of abscission." (2013). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 71.
https://jdc.jefferson.edu/bmpfp/71

PubMed ID

23885121