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LZTR1 is a regulator of RAS ubiquitination and signaling

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Science  15 Nov 2018:
eaap8210
DOI: 10.1126/science.aap8210

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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 (LZTR1) gene led to enhanced mitogen-activated protein kinase pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a RAS-dependent gain of function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS. We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. As LZTR1 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for LZTR1 involvement in a variety of inherited and acquired human disorders.

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