Prof. Guangshuo Ou’s group from the School of Life Sciences at Tsinghua University published a paper entitled “Hippo kinases maintain polarity during directional cell migration in Caenorhabditis elegans” on The EMBO Journal on Feb. 1st, 2017. Their work showed that Hippo kinase and RhoG/MIG-2 function in a negative feedback loop to maintain the polarity of the directional migrating cell.
Directional cell migration is essential for metazoan development, immune responses, wound healing and other processes. The disruption of cell migration contributes to diseases including cancer invasion and metastasis. Abnormal neuronal positioning leads to cortical development malformation and neuropsychiatric diseases. The migrating cell responses to the attractive cues and stimulates the local activity of Rac GTPases that facilitate the actin polymerization and membrane protrusion in the leading edge. However, the Rac GTPases are evenly distributed along the cell periphery and has the potential to active at any loci. The repulsive mechanisms that prevent the formation of secondary leading edges by restricting Rac GTPase activity remain largely unclear.
Prof. Ou and his colleagues found that C. elegans Hippo kinases promote cell migration along the anterior–posterior body axis by inhibiting the dorsal–ventral (DV) migration. Ectopic DV polarization was also demonstrated in gain-of-function mutant animals for C. elegans RhoG MIG-2. They identified serine 139 of MIG-2 as a novel conserved Hippo kinase phosphorylation site and demonstrated that purified Hippo kinases directly phosphorylate MIG-2S139. Live imaging analysis of genome-edited animals indicates that MIG-2S139 phosphorylation impedes actin assembly in migrating cells. Intriguingly, Hippo kinases are excluded from the leading edge in wild-type cells, while MIG-2 loss induces uniform distribution of Hippo kinases. They provide evidence that Hippo kinases inhibit RhoG activity locally and are in turn restricted to the cell body by RhoG-mediated polarization.
Fig. 1. The proposed model of Hippo-RhoG negative feedback loop.
Prof. Ou from the School of Life Sciences at Tsinghua University is the corresponding author. PhD student Guoxin Feng from Tsinghua-Peking Center for Life Sciences is the first author of this paper. Prof. Meng-Qiu Dong and Dr. Wen-Jun Li from National Institute of Biological Sciences performed the Mass spectrometry analysis. Zhiwen Zhu, Qirong Lin and Dr. Yongping Chai from the School of Life Sciences at Tsinghua University participated in this project. This research was funded by Tsinghua-Peking Center for Life Sciences, the National Natural Science Foundation of China and the National Basic Research Program of China (973 Program).
Paper link: http://emboj.embopress.org/content/36/3/334