LZTR1, or leucine zipper-like transcriptional regulator 1, is an adaptor for the cullin 3 (CUL3) ubiquitin ligase complex. It plays a crucial role in regulating RAS ubiquitination, which in turn impacts the mitogen-activated protein kinase (MAPK) pathway. By modulating RAS signaling, LZTR1 is involved in various biological processes, and its dysregulation is associated with human diseases [1,2].

LZTR1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, while LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. Loss of Lztr1 in mice abrogates Ras ubiquitination at lysine-170, and LZTR1-mediated ubiquitination inhibits RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupt either LZTR1-CUL3 complex formation or its interaction with RAS proteins [1]. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system causes tumors in the peripheral nervous system, recapitulating aspects of schwannomatosis [3].

In conclusion, LZTR1 is essential for regulating RAS ubiquitination and MAPK pathway activation. Studies using mouse models, such as gene knockout (KO) and conditional knockout (CKO) models, have revealed its role in Noonan syndrome and schwannomatosis. These models provide valuable insights into the mechanisms of LZTR1-related diseases, facilitating a better understanding of the underlying biological processes and potentially guiding the development of therapeutic strategies for these conditions.