CEMIP, acting as a scaffold protein for bridging GRAF1 and MIB1, promotes colorectal cancer metastasis via activating CDC42/MAPK pathway

Metastasis is the leading cause of treatment failure and tumor-related death in colorectal cancer (CRC). Our previous studies report that CEMIP functionally promotes CRC metastasis and is closely related to poor outcomes. However, the molecular network of CEMIP promoting CRC metastasis is still not fully understood. In the current study, we identify CEMIP interacting with GRAF1, and the combination of high-CEMIP and low-GRAF1 predicts poor survival of patients. Mechanistically, we elucidate that CEMIP interacts with the SH3 domain of GRAF1 through the 295–819aa domain, and negatively regulates the stability of GRAF1. Moreover, we identify MIB1 to be an E3 ubiquitin ligase for GRAF1. Importantly, we uncover that CEMIP acts as a scaffold protein in bridging MIB1 and GRAF1, which is critical to GRAF1 degradation and CEMIP-mediated CRC metastasis. Furthermore, we found that CEMIP activates CDC42/MAPK pathway-regulated EMT by enhancing the degradation of GRAF1, which is indispensable to CEMIP-mediated migration and invasion of CRC cells. Subsequently, we prove that CDC42 inhibitor suppresses CEMIP-mediated CRC metastasis in vitro and in vivo. Collectively, our results reveal that CEMIP promotes CRC metastasis through GRAF1/CDC42/MAPK pathway-regulated EMT, and suggest that CDC42 inhibitor could be a novel therapeutic strategy for CEMIP-mediated CRC metastasis. [Image: see text]