LZTR1 is a regulator of RAS ubiquitination and signaling.
Science
; 362(6419): 1171-1177, 2018 12 07.
Article
em En
| MEDLINE
| ID: mdl-30442766
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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Proteínas Proto-Oncogênicas p21(ras)
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Ubiquitinação
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article