LZTR1 Is a Regulator of RAS Ubiquitination and Signaling

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Drosophila melanogaster
  • Drug Resistance, Neoplasm / genetics
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Gain of Function Mutation
  • Gene Knockdown Techniques
  • Humans
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / epidemiology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Loss of Function Mutation
  • MAP Kinase Signaling System / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Pyridazines / pharmacology
  • Pyridazines / therapeutic use
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Ubiquitination* / genetics

Substances

  • Antineoplastic Agents
  • Imidazoles
  • KRAS protein, human
  • LZTR1 protein, human
  • Protein Kinase Inhibitors
  • Pyridazines
  • Transcription Factors
  • ponatinib
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins p21(ras)