Format

Send to

Choose Destination
Science. 2018 Dec 7;362(6419):1171-1177. doi: 10.1126/science.aap8210. Epub 2018 Nov 15.

LZTR1 is a regulator of RAS ubiquitination and signaling.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
2
Department of Cell, Developmental, and Regenerative Biology and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.
3
Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
4
Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
5
Oncode Institute, Division of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
6
Cancer Genomics Center (CGC.nl), Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
7
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. gsuperti@cemm.oeaw.ac.at.
8
Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

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 (MAPK) 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 (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 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.

PMID:
30442766
DOI:
10.1126/science.aap8210

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center