The Anaphase-Promoting Complex/Cyclosome Activator Cdh1 Modulates Rho GTPase by Targeting p190 RhoGAP for Degradation

Cdh1 is an activator of the anaphase-promoting complex/cyclosome and contributes to mitotic exit and G1 maintenance by targeting cell cycle proteins for degradation. However, Cdh1 is expressed and active in postmitotic or quiescent cells, suggesting that it has functions other than cell cycle control. Here, we found that homozygousCdh1 gene-trapped (Cdh1 GT/GT ) mouse embryonic fibroblasts (MEFs) andCdh1 -depleted HeLa cells reduced stress fiber formation significantly. The GTP-bound active Rho protein was apparently decreased in theCdh1 -depleted cells. The p190 protein, a major GTPase-activating protein for Rho, accumulated both inCdh1 GT/GT MEFs and inCdh1 -knockdown HeLa cells. Cdh1 formed a physical complex with p190 and stimulated the efficient ubiquitination of p190, both inin vitro andin vivo . The motility ofCdh1 -depleted HeLa cells was impaired; however, codepletion of p190 rescued the migration activity of these cells. Moreover,Cdh1 GT/GT embryos exhibited phenotypes similar to those observed for Rho-associated kinase I and II knockout mice: eyelid closure delay and disruptive architecture with frequent thrombus formation in the placental labyrinth layer, respectively. Furthermore, the p190 protein accumulated in theCdh1 GT/GT embryonic tissues. Our data revealed a novel function for Cdh1 as a regulator of Rho and provided insights into the role of Cdh1 in cell cytoskeleton organization and cell motility.