Mutations of the LZTR1 gene are involved in the development of tumors and both, autosomal dominant and autosomal recessive variants have been described to cause Noonan syndrome. Yet, how exactly its encoded protein, leucine zipper–like transcriptional regulator 1, acts has so far remained elusive.

Now two studies published in Science shed light on the function of the LZTR1 protein. For one, they showed that in a mouse model heterozygous LZTR1 mutations caused a phenotype that recapitulates various aspects of Noonan syndrome in humans. On a biochemical level, the researchers determined that LZTR1 associates with the small G-protein RAS. It appears to act as an adapter promoting ubiquitination of RAS proteins, thus diminishing signal transduction in the mitogen-activated protein kinase (MAPK) pathway. LZTR1 mutations, by contrast, seem to decrease ubiquitination of RAS proteins. These results were supplemented by the findings of another study, which demonstrated that loss of LZTR1 protein function led to enhanced RAS activity and MAPK pathway activation and reduced sensitivity to tyrosine kinase inhibitors. The RAS-MAPK pathway is a central signaling cascade that regulates and controls elementary cell functions. The new findings uncovering the functional mechanism of LZTR1 may therefore explain the protein’s involvement in the pathogenesis of various diseases and might be the basis for future development of novel therapeutic approaches.