Oncogenic B-RafV600E abrogates the AKT/B-Raf/Mps1 interaction in melanoma cells

• A novel auto-regulatory negative feedback loop exists between Mps1 and B-Raf/ERK signaling.
• Oncogenic B-RafV600E abrogates the negative feedback loop between Mps1 and B-Raf/ERK pathway.
• AKT is critical for the regulatory negative feedback loop of Mps1 on the B-RafWT/ERK pathway.
• B-RafV600E prevents AKT phosphorylation, contributing abrogation of the negative feedback loop of Mps1 on MAPK pathway.

Activating B-Raf mutations that deregulate the mitogen-activated protein kinase (MAPK) pathway commonly occur in cancer. Although B-RafV600E induces increased Mps1 protein contributing to centrosome amplification and chromosome instability, the regulatory mechanisms of Mps1 in melanoma cells is not fully understood. Here, we report that Mps1/AKT and B-RafWT/ERK signaling form an auto-regulatory negative feedback loop in melanoma cells; notably, oncogenic B-RafV600E abrogates the negative feedback loop, contributing the aberrant Mps1 functions and tumorigenesis. Our findings raise the possibility that targeting the oncogenic B-Raf and Mps1, especially when used in combination could potentially provide great therapeutic opportunities for cancer treatment.