Controlling the switches: Rho GTPase regulation during animal cell mitosis

Abstract

Animal cell division is a fundamental process that requires complex changes in cytoskeletal organization and function. Aberrant cell division often has disastrous consequences for the cell and can lead to cell senescence, neoplastic transformation or death. As important regulators of the actin cytoskeleton, Rho GTPases play major roles in regulating many aspects of mitosis and cytokinesis. These include centrosome duplication and separation, generation of cortical rigidity, microtubule-kinetochore stabilization, cleavage furrow formation, contractile ring formation and constriction, and abscission. The ability of Rho proteins to function as regulators of cell division depends on their ability to cycle between their active, GTP-bound and inactive, GDP-bound states. However, Rho proteins are inherently inefficient at fulfilling this cycle and require the actions of regulatory proteins that enhance GTP binding (RhoGEFs), stimulate GTPase activity (RhoGAPs), and sequester inactive Rho proteins in the cytosol (RhoGDIs). The roles of these regulatory proteins in controlling cell division are an area of active investigation. In this review we will delineate the current state of knowledge of how specific RhoGEFs, RhoGAPs and RhoGDIs control mitosis and cytokinesis, and highlight the mechanisms by which their functions are controlled.

Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-Activating Proteins in Basal-like Breast Cancers

“…RacGAP1 has a well-documented role in regulating cytokinesis (29,30), and ArhGAP11A has also recently been implicated in the control of this process (31). We therefore examined the effect of GAP-knockdown on the efficiency of BLBC cell division.…”

“…In BLBC, we found that RacGAP1-depleted cells failed to proliferate as a result of cytokinesis failure, p21-induction, and the onset of senescence. The role of RacGAP1 in regulating cytokinesis is well-established (29,30) and, in BLBC, high levels of this protein may be required to facilitate excessive cell division. The GTPase specificity of RacGAP1 is controversial, with one study suggesting that this GAP could be converted from a Rac1- to a RhoA-specific GAP upon phosphorylation by aurora kinase B (50).…”

RND1 is up-regulated in esophageal squamous cell carcinoma and promotes the growth and migration of cancer cells

“…Activation of Rho GTPase is stimulated by guanine nucleotide exchange factors (GEF) and inhibited by GTPase activating proteins (GAP) [1][2][3].…”

Mitotic-dependent phosphorylation of leukemia-associated RhoGEF (LARG) by Cdk1

“…Cyclin B is degraded as cells progress through anaphase towards the end of mitosis, leading again to the inactivation Cdk1 [25]. Mitotic Cdk1/cyclin B phosphorylates and regulates a myriad of key mitotic proteins, including the mitotic RhoGEFs Ect2, GEF-H1, and MyoGEF [26]. For example, phosphorylation of GEF-H1 by Cdk1, along with Aurora A kinase, during early mitosis inhibits GEF-H1, while dephosphorylation of GEF-H1, temporally coinciding with Cdk1 inactivation, prior to cytokinesis activates GEF-H1, thus promoting activation of RhoA [6].…”