Mts/ <scp>PP2AC</scp> Induces Cell Migration via Rho1‐Slpr‐Mediated <scp>JNK</scp> Pathway

Cell migration plays crucial roles in cancer generation and metastasis. A deeper understanding of the mechanisms that govern this migratory behavior may uncover novel drug targets that could be utilized in cancer treatments. PP2AC, the catalytic subunit of protein phosphatase 2A, has been found to be expressed in various human cancers. However, the specific role of PP2AC in the context of cancer cell migration has remained elusive. In this study, we demonstrated that Mts (the ortholog of PP2AC in Drosophila) is sufficient to trigger cell migration through activating the JNK pathway. Genetic epistasis analyses data revealed that Mts acts upstream of Slpr in the JNK signaling cascade. Furthermore, we identified Rho1 as a candidate mediator through affinity purification-mass spectrometry (AP-MS), which functions downstream of Mts in the Slpr-JNK signaling cascade supported by genetic evidence. Consistently, our results revealed that Mts activates the JNK signaling pathway by increasing the protein level of Rho1. Finally, we showed that PP2AC promotes cell migration in human pancreatic adenocarcinoma (PAAD) cells and is associated with RhoA levels and JNK activation. Taken together, our research supports a model in which Mts/PP2AC functions as an upstream regulator of the Rho1-JNK signaling axis in cell migration and offers promising therapeutic strategies to combat cancer metastasis.