Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

Mutations in RAS proteins initiate many of the most aggressive tumors, and the search for pharmacological inhibitors of these proteins has become a priority in the battle against cancer. Researchers have identified LZTR1 as an evolutionarily conserved component of the RAS pathway.

Multiple genetic studies overwhelmingly point out for 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 nerves. The researchers found that LZTR1 contributes to human diseases by acting as a part of the ubiquitin ligase complex that mediates conjugation of ubiquitin to RAS proteins. This conjugation reduces RAS recruitment to the membrane and thus its activation and downstream signalling.

By trapping LZTR1 complexes from intact mammalian cells, authors identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine 170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane.
Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation, or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.
Senior author said: "Despite of constant and exhaustive efforts to characterize RAS proteins, LZTR1 is the first novel RAS regulator, implicated in human diseases, that has been identified since years. We hope that the discovery of this alternative mechanism of RAS regulation will lead toward novel therapeutic approaches for RAS-driven diseases."