Novel cytokinetic ring components drive negative feedback in cortical contractility

Actomyosin cortical contractility drives many cell shape changes including cytokinetic furrowing. While positive regulation of contractility is well characterized, counterbalancing negative regulation and mechanical brakes are less well understood. The small GTPase RhoA is a central regulator, activ...

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Veröffentlicht in:Molecular biology of the cell 2020-07, Vol.31 (15), p.1623-1636
Hauptverfasser: Bell, Kathryn Rehain, Werner, Michael, Doshi, Anusha, Cortes, Daniel, Sattler, Adam, Vuong-Brender, Thanh, Labouesse, Michel, Maddox, Amy Shaub
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container_end_page 1636
container_issue 15
container_start_page 1623
container_title Molecular biology of the cell
container_volume 31
creator Bell, Kathryn Rehain
Werner, Michael
Doshi, Anusha
Cortes, Daniel
Sattler, Adam
Vuong-Brender, Thanh
Labouesse, Michel
Maddox, Amy Shaub
description Actomyosin cortical contractility drives many cell shape changes including cytokinetic furrowing. While positive regulation of contractility is well characterized, counterbalancing negative regulation and mechanical brakes are less well understood. The small GTPase RhoA is a central regulator, activating cortical actomyosin contractility during cytokinesis and other events. Here we report how two novel cytokinetic ring components, GCK-1 (germinal center kinase-1) and CCM-3 (cerebral cavernous malformations-3), participate in a negative feedback loop among RhoA and its cytoskeletal effectors to inhibit contractility. GCK-1 and CCM-3 are recruited by active RhoA and anillin to the cytokinetic ring, where they in turn limit RhoA activity and contractility. This is evidenced by increased RhoA activity, anillin and nonmuscle myosin II in the cytokinetic ring, and faster cytokinetic furrowing, following depletion of GCK-1 or CCM-3. GCK-1 or CCM-3 depletion also reduced RGA-3 levels in pulses and increased baseline RhoA activity and pulsed contractility during zygote polarization. Together, our results suggest that GCK-1 and CCM-3 regulate cortical actomyosin contractility via negative feedback. These findings have implications for the molecular and cellular mechanisms of cerebral cavernous malformation pathologies.
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While positive regulation of contractility is well characterized, counterbalancing negative regulation and mechanical brakes are less well understood. The small GTPase RhoA is a central regulator, activating cortical actomyosin contractility during cytokinesis and other events. Here we report how two novel cytokinetic ring components, GCK-1 (germinal center kinase-1) and CCM-3 (cerebral cavernous malformations-3), participate in a negative feedback loop among RhoA and its cytoskeletal effectors to inhibit contractility. GCK-1 and CCM-3 are recruited by active RhoA and anillin to the cytokinetic ring, where they in turn limit RhoA activity and contractility. This is evidenced by increased RhoA activity, anillin and nonmuscle myosin II in the cytokinetic ring, and faster cytokinetic furrowing, following depletion of GCK-1 or CCM-3. GCK-1 or CCM-3 depletion also reduced RGA-3 levels in pulses and increased baseline RhoA activity and pulsed contractility during zygote polarization. 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title Novel cytokinetic ring components drive negative feedback in cortical contractility
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