USP8 modulates ubiquitination of LRIG1 for Met degradation
Journal
Scientific Reports
Date
2014.05.15
Abstract
The Met receptor tyrosine kinase is an attractive target for cancer therapy and promotes invasive tumor growth. SAIT301 was developed as a novel anti-Met antibody, which induced LRIG1-mediated Met degradation and inhibited tumor growth while avoiding agonism. However, detailed downstream mechanism by which LRIG1 mediates target protein down-regulation is unknown. In the present study, we discovered that SAIT301 induces ubiquitination of LRIG1 and this serves as a signal for lysosomal degradation. Ubiquitination of LRIG1 promotes recruitment of Met and LRIG1 complex to lysosome through its interaction with Hrs, resulting in concomitant degradation of both LRIG1 and Met. We also identified USP8 as a LRIG1-specific deubiquitinating enzyme, reporting the interaction between USP8 and LRIG1 for the first time. SAIT301 triggers degradation of LRIG1 by inhibiting the interaction of LRIG1 and USP8, which regulates ubiquitin modification and stability of LRIG1. In summary, a Met targeting antibody, SAIT301 employs ubiquitination of LRIG1 for its highly effective Met degradation. This unique feature of SAIT301 enables it to function as a full antagonistic antibody without triggering downstream Met signaling. We found that USP8 is involved in deubiquitination of LRIG1, regulating the efficiency of Met degradation. The relation of Met, LRIG1 and USP8 strongly supports the potential clinical benefit of combination treatment of a USP8 inhibitor and an anti-Met antibody, such as SAIT301.