2. Academic Validation
  3. LZTR1 is a regulator of RAS ubiquitination and signaling

LZTR1 is a regulator of RAS ubiquitination and signaling

  • Science. 2018 Dec 7;362(6419):1171-1177. doi: 10.1126/science.aap8210.
Johannes W Bigenzahn 1,  Giovanna M Collu 2,  Felix Kartnig 1,  Melanie Pieraks 1,  Gregory I Vladimer 1,  Leonhard X Heinz 1,  Vitaly Sedlyarov 1,  Fiorella Schischlik 1,  Astrid Fauster 1 3,  Manuele Rebsamen 1,  Katja Parapatics 1,  Vincent A Blomen 3,  André C Müller 1,  Georg E Winter 1,  Robert Kralovics 1 4,  Thijn R Brummelkamp 1 3 5 6,  Marek Mlodzik 2,  Giulio Superti-Furga 7 8
Affiliations

Affiliations

  • 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.
PMID: 30442766 DOI: 10.1126/science.aap8210
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.

Figures