LZTR1 is a Regulator of RAS Ubiquitination and Signaling

Overview

Journal Science

Specialty Science

Date 2018 Nov 17

PMID 30442766

Citations 104

Authors

Johannes W Bigenzahn

Giovanna M Collu

Felix Kartnig

Melanie Pieraks

Gregory I Vladimer

Leonhard X Heinz

Vitaly Sedlyarov

Fiorella Schischlik

Astrid Fauster

Manuele Rebsamen

Katja Parapatics

Vincent A Blomen

Andre C Muller

Georg E Winter

Robert Kralovics

Thijn R Brummelkamp

Marek Mlodzik

Giulio Superti-Furga

Affiliations

Soon will be listed here.

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 () gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the ortholog resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of 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 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for involvement in a variety of inherited and acquired human disorders.

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