Leucine-zipper-like transcriptional regulator 1 (LZTR1)

Leucine-zipper-like transcriptional regulator 1 (LZTR1) is a BTB-Kelch family protein that functions as an adaptor for the Cullin 3 (CUL3)-based E3 ubiquitin ligase complex, facilitating the polyubiquitination and degradation of RAS family small GTPases, such as KRAS, NRAS, HRAS, RIT1, and RAF1. LZTR1 acts as a negative regulator of the RAS/MAPK signaling pathway and plays a critical role in the regulation of cell proliferation, cell cycle progression, and tumor suppression by targeting oncogenic RAS proteins for degradation. Mutations in LZTR1 reduce its protein-protein interactions and substrate fidelity, leading to persistent RAS signaling, increased cell proliferation, and development of diseases including glioblastoma, chronic myeloid leukemia, schwannomatosis, and Noonan syndrome. Although initially named for weak homology to transcription regulators, LZTR1 is not a classical transcription factor but is localized primarily to the Golgi apparatus. There are currently no approved drugs directly targeting LZTR1, but its functional axis with RAS proteins is a focus for future targeted therapies.

Other names

BTBD29LZTR-1TCFL2NS10NS2SWNTS2epididymis secretory sperm binding proteinleucine zipper like transcription regulator 1

For RAS pathway drugs: Inhibition of RAS/MAPK signaling by promoting ubiquitination and degradation of RAS proteins. Potential future mechanisms: Modulation of E3 ligase function to restore tumor suppressor activity in cells with LZTR1 loss-of-function mutations.