Shared mechanisms regulate spatiotemporal RhoA-dependent actomyosin contractility during adhesion and cell division

Abstract

Local modulation of the actin cytoskeleton is essential for the initiation and maintenance of strong homotypic adhesive interfaces between neighboring cells. The epithelial adherens junction (AJ) fulfils a central role in this process by mediating E-cadherin interactions and functioning as a signaling scaffold to control the activity of the small GTPase RhoA and subsequent actomyosin contractility. Interestingly, a number of regulatory proteins that modulate RhoA activity at the AJ also control RhoA during cytokinesis, an actomyosin-dependent process that divides the cytoplasm to generate two daughter cells at the final stages of mitosis. Recent insights have revealed that the central player in AJ stability, p120-catenin (p120), interacts with and modulates essential regulators of actomyosin contraction during cytokinesis. In cancer, loss of this modulation is a common event during tumor progression that can induce chromosomal instability and tumor progression.In this review, we will highlight the functional differences and similarities of the different RhoA-associated factors that have been linked to both the regulation of cell-cell adhesion and cytokinesis.

Keywords: Rho activity; actomyosin contractility; cell adhesion; cytokinesis; p120-catenin.

Figure 1.

Activity of Rho GTPase family members is compartementalized during cell division. (A) During mitosis and cytokinesis, the activity and localization of RhoA, Rac1 and Cdc42 is compartimentalized. Cdc42 activity peaks during metaphase where it is involved in the attachement of microtubules to the kinetochores. While the overall levels of active Rac1 do not change during cell division, its inactivation at the equatorial cortex is necessary for cytokinesis completions. Here, RhoA activity peaks during anaphase and telophase and drives the ingression of the cleavage furrow. Rac1 activity at the polar regions is thought to contribute to cell spreading and adhesion during and/or after cytokinesis. Both positive (including the RhoGEF Ect2) and negative regulators (including p120 and its interaction partner the RhoGAP MP-GAP; see text for more details) of RhoA localize to the equatorial cortex during cleavage furrow ingression to allow for rapid GTPase cycling to restrict and focus activity of RhoA. (B) Our recent data suggest that an inactive RhoA pool (marked by phosphorylation of Ser188) exists directly adjacent to the active membrane-associated RhoA pool during furrow ingression (anaphase to telophase)³⁸ _. The presence of this substantial pool of inactive RhoA might enable rapid GTPase cycling of RhoA to maintain heavily restricted RhoA activity at the eqeatorial cortex to drive the ingression of the cleavage furrow. The molecular mechanisms underlying phosphorylation of RhoA during cytokineses remain undetermined. The two future daughter cells are indicated with I. and II. Error bar = 2 μm. Immunofluorescence images depicted here are reproduced from³⁸.

Figure 2.

Shared machinery controls Rho GTPases during adhesion and cytokinesis. (A) Regulation of Rho GTPases in cell-cell adhesion complexes. The adherens junction (AJ) complex serves as an adhesion and signaling scaffold that regulates the Rho GTPases. Centralspindlin binds α-catenin and delivers RhoGEF activity via Ect2 to the AJ. In contrast, p120 negatively regulates RhoA activity at the AJ either through recruitment of p190B RhoGAP or through direct binding of inactive GDP-bound RhoA. The presence of centralspindlin at the AJ in turn inhibits the recruitment of p190B RhoGAP to the junction and provides GAP activity towards Rac1 through MgcRacGAP. In turn, the RacGEF Vav2 is recruited to p120 and positively regulates Rac1 near the junction. Besides its function at the AJ, Ect2 has also been associated with regulation of Cdc42 activity at the tight junction (TJ). (B) At the equatorial cortex, local RhoA activity drives ingression of the cleavage furrow. Centralspindlin localizes to the spindle midzone (also known as central spindle; CS) and equatorial cortex through association with both overlapping parallel and astral microtubules (MT). Ect2 is then recruited to centralspindlin and acts as a key RhoGEF during cytokinesis. In addition, the RhoGEF activity of GEF-H1 is necessary during later stages of cytokinesis. The interaction between RhoA and Ect2 is stabilized by the catenin p0071. Another catenin, p120, regulates RhoA activity through complex formation with MP-GAP and GDP-bound RhoA, which might facilitate its N-terminal association with centralspindlin through MKLP1. The presence of positive and negative regulators of RhoA activity near the equatorial cortex provides rapid GTPase cycling and controls the spatial distribution of the active RhoA zone needed for cytokinesis.