LZTR1 is a regulator of RAS ubiquitination and signaling

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 33

Record: found
Abstract: found
Article: found

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

(2017)

Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.

0 comments Cited 916 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The CRAPome: a Contaminant Repository for Affinity Purification Mass Spectrometry Data

Dattatreya Mellacheruvu, Zachary Wright, Amber L Couzens … (2013)

Affinity purification coupled with mass spectrometry (AP-MS) is now a widely used approach for the identification of protein-protein interactions. However, for any given protein of interest, determining which of the identified polypeptides represent bona fide interactors versus those that are background contaminants (e.g. proteins that interact with the solid-phase support, affinity reagent or epitope tag) is a challenging task. While the standard approach is to identify nonspecific interactions using one or more negative controls, most small-scale AP-MS studies do not capture a complete, accurate background protein set. Fortunately, negative controls are largely bait-independent. Hence, aggregating negative controls from multiple AP-MS studies can increase coverage and improve the characterization of background associated with a given experimental protocol. Here we present the Contaminant Repository for Affinity Purification (the CRAPome) and describe the use of this resource to score protein-protein interactions. The repository (currently available for Homo sapiens and Saccharomyces cerevisiae) and computational tools are freely available online at www.crapome.org.

0 comments Cited 647 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

RAS Proteins and Their Regulators in Human Disease.

Dhirendra Simanshu, Dwight Nissley, Frank McCormick (2017)

RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS' interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.