Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens

Abstract

The biological impact of Rho depends critically on the precise subcellular localization of its active, GTP-loaded form. This can potentially be determined by the balance between molecules that promote nucleotide exchange or GTP hydrolysis. However, how these activities may be coordinated is poorly understood. We now report a molecular pathway that achieves exactly this coordination at the epithelial zonula adherens. We identify an extramitotic activity of the centralspindlin complex, better understood as a cytokinetic regulator, which localizes to the interphase zonula adherens by interacting with the cadherin-associated protein, α-catenin. Centralspindlin recruits the RhoGEF, ECT2, to activate Rho and support junctional integrity through myosin IIA. Centralspindlin also inhibits the junctional localization of p190 B RhoGAP, which can inactivate Rho. Thus, a conserved molecular ensemble that governs Rho activation during cytokinesis is used in interphase cells to control the Rho GTPase cycle at the zonula adherens.

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Figure 1: The zonula adherens is a microtubule-dependent Rho zone.
Figure 2: ECT2 is a junctional RhoA GEF.
Figure 3: ECT2 is necessary for zonula adherens integrity and junctional tension.
Figure 4: Centralspindlin regulates junctional ECT2–Rho signalling.
Figure 5: α-catenin mediates the junctional retention of ECT2.
Figure 6: α-catenin mediates the junctional retention of centralspindlin.
Figure 7: Centralspindlin inhibits the junctional recruitment of p190B RhoGAP.

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Acknowledgements

We thank our laboratory colleagues for their support and advice, all our colleagues who provided gifts of reagents, and R. Saint who first suggested we think about ECT2. This work was financially supported by the Human Frontiers Science Program, the National Health and Medical Research Council of Australia, Australian Research Council, and the Oncology Children’s Foundation. Confocal microscopy was performed at the IMB/ACRF Cancer Biology Imaging Facility, established with the generous support of the Australian Cancer Research Foundation.

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A.R., S.J.S., A.A. and A.S.Y. conceived the project, A.R., G.A.G., R.P., S.V. and N.H.B. conducted experiments, E.M.K. and K.J. generated reagents, A.R., G.A.G. and A.S.Y. analysed the data and A.R. and A.S.Y. wrote the paper.

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Correspondence to Aparna Ratheesh or Alpha S. Yap.

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The authors declare no competing financial interests.

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Ratheesh, A., Gomez, G., Priya, R. et al. Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens. Nat Cell Biol 14, 818–828 (2012). https://doi.org/10.1038/ncb2532

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