LZTR1 is a regulator of RAS ubiquitination and signaling.
Johannes W BigenzahnGiovanna M ColluFelix KartnigMelanie PieraksGregory I VladimerLeonhard X HeinzVitaly SedlyarovFiorella SchischlikAstrid FausterManuele RebsamenKatja ParapaticsVincent A BlomenAndré C MüllerGeorg E WinterRobert KralovicsThijn R BrummelkampMarek MlodzikGiulio Superti-FurgaPublished in: Science (New York, N.Y.) (2018)
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.
Keyphrases
- wild type
- transcription factor
- chronic myeloid leukemia
- endothelial cells
- oxidative stress
- genome wide
- signaling pathway
- induced apoptosis
- copy number
- squamous cell carcinoma
- clinical trial
- pi k akt
- gene expression
- small molecule
- pluripotent stem cells
- cell proliferation
- high throughput
- endoplasmic reticulum stress
- dna methylation
- cell cycle arrest
- cell death
- binding protein
- genome wide identification