Changes in Ect2 Localization Couple Actomyosin-Dependent Cell Shape Changes to Mitotic Progression

Abstract

SummaryAs they enter mitosis, animal cells undergo profound actin-dependent changes in shape to become round. Here we identify the Cdk1 substrate, Ect2, as a central regulator of mitotic rounding, thus uncovering a link between the cell-cycle machinery that drives mitotic entry and its accompanying actin remodeling. Ect2 is a RhoGEF that plays a well-established role in formation of the actomyosin contractile ring at mitotic exit, through the local activation of RhoA. We find that Ect2 first becomes active in prophase, when it is exported from the nucleus into the cytoplasm, activating RhoA to induce the formation of a mechanically stiff and rounded metaphase cortex. Then, at anaphase, binding to RacGAP1 at the spindle midzone repositions Ect2 to induce local actomyosin ring formation. Ect2 localization therefore defines the stage-specific changes in actin cortex organization critical for accurate cell division.

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“…The construction of an actin cortex in early mitosis also likely sets the stage for the cell shape changes that occur at cytokinesis, when actomyosin ring contraction and polar relaxation cleave the cell into two [21], since both processes rely on a common set of cortical regulators [14,16,22]. In addition, and most significant for this discussion, the rigid and rounded cortex creates a protective space in which to construct a spindle and segregate chromosomes, buffering mitosis from external forces [17].…”

“…Similarly, cells round up and push aside their neighbors as they enter mitosis when dividing in the context of a crowded epithelium [14,15]. Cells undergo a similar process of mitotic swelling even when dividing in suspension [16]. These shape changes, both in cell culture and in vivo [15], depend on the actin cytoskeleton, which is re-organized upon mitotic entry to form a cortical mesh that underlies the plasma membrane [17].…”

“…These shape changes, both in cell culture and in vivo [15], depend on the actin cytoskeleton, which is re-organized upon mitotic entry to form a cortical mesh that underlies the plasma membrane [17]. As well as driving cell shape change, the re-organization of cortical actin in mitosis also counters osmotic swelling forces [18] and provides mitotic cells with their characteristic mechanical rigidity [16,19].…”

“…The process of actin-dependent mitotic rounding is essential for the proper formation and positioning of the mitotic spindle [16,17,19,20]. The construction of an actin cortex in early mitosis also likely sets the stage for the cell shape changes that occur at cytokinesis, when actomyosin ring contraction and polar relaxation cleave the cell into two [21], since both processes rely on a common set of cortical regulators [14,16,22].…”

“…A number of pathways are involved, likely acting in parallel, downstream of the mitotic kinase, Cdk1 [16]. The focal adhesion complexes that act as points of attachment to the ECM are disassembled, in a process dependent on inactivation of the small GTPase Rap1 [23].…”