LZTR1 is a regulator of RAS ubiquitination and signaling.

Abstract

In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (<i>LZTR1</i>) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the <i>Drosophila LZTR1</i> ortholog <i>CG3711</i> resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of <i>LZTR1</i> led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because <i>LZTR1</i> disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for <i>LZTR1</i> involvement in a variety of inherited and acquired human disorders.