Mutations in RAS proteins start many of the more aggressive tumors, and the search for pharmacological inhibitors of these proteins has become a priority in the battle against cancer. Michail Steklov, Francesca Baietti and colleagues at the Anna Sablina Laboratory (VIB-KU Leuven Center for Cancer Biology) have identified LZTR1 as an evolutionarily conserved component of the RAS pathway.
Multiple genetic studies point emphatically to the role of LZTR1 in a wide range of human disorders such as Noonan Syndrome (a genetic disease), liver cancer, childhood cancer and Schwannoma, a benign tumor that affects the nerves. The researchers found that LZTR1 contributes to human diseases by acting as part of the ubiquitin ligase complex that mediates the ubiquitin conjugation to RAS proteins. This conjugation reduces the recruitment of RAS to the membrane and hence its activation and downstream signaling.
Prof. Anna Sablina (VIB-KU Leuven): "Despite the constant and exhaustive efforts to characterize RAS proteins, LZTR1 is the first innovative RAS regulator implicated in human disease, which has been identified for years. the help of our collaborators from UZ Leuven, the VIB-UGent Biotechnology Medical Center, the Frederick National Cancer Institute and the University of Alabama. We hope that the discovery of this alternative mechanism of RAS regulation leads to new therapeutic approaches for RAS- directed ".