ArticleCell death and differentiation2020
LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases.
Article in Cell death and differentiation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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77 citing papers in PubMed, 125 citations in OpenAlex.
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- Structural basis for LZTR1 recognition of RAS GTPases for degradation.Science (New York, N.Y.) · 2025Article
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- Multi-omics integration and machine learning uncover molecular basal-like subtype of pancreatic cancer and implicate A2ML1 in promoting tumor epithelial-mesenchymal transition.Journal of translational medicine · 2025Article
- LZTR1 expression as a novel predictive biomarker for early recurrence of hepatocellular carcinoma.European journal of medical research · 2025Article
- Ubiquitination in hepatocellular carcinoma immunity.Journal of translational medicine · 2025Review
- Protein-losing enteropathy and multiple vasculature dysplasia inWorld journal of gastroenterology · 2025Review
- Genetic Basis and Clinical Management of Schwannomatosis.Journal of Korean Neurosurgical Society · 2025Article
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- Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer.Nature communications · 2025Article
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- Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development.Nature communications · 2025Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. Mutations in LZTR1 have been identified in glioblastoma, schwannomatosis, and Noonan syndrome. However, the functional role of LZTR1 in carcinogenesis or human development is not fully understood. Here, we demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway, leading to the inhibition of the RAS/MAPK signaling. The polyubiquitination and degradation of RAS was also observed in cells expressing MRAS, HRAS, NRAS, and KRAS as well as oncogenic RAS mutants and inhibited the activation of ERK1/2 and cell growth. In vivo ubiquitination assays showed that MRAS-K127 and HRAS-K170 were ubiquitinated by LZTR1 and that the polyubiquitinated-chains contained mainly Ub-K48, K63, and K33-linked chains, suggesting its possible involvement in autophagy. Immunoprecipitation analyses showed the interaction of LZTR1 and RAS-GTPases with autophagy-related proteins, including LC3B and SQSTM1/p62. Co-expression of LZTR1 and RAS increased the expression of lipidated form of LC3B. However, long-term treatment with chloroquine had little effect on RAS protein levels, suggesting that the contribution of autophagy to LZTR1-mediated RAS degradation is minimal. Taken together, these results show that LZTR1 functions as a "RAS killer protein" mainly via the ubiquitin-proteasome pathway regardless of the type of RAS GTPase, controlling downstream signal transduction. Our results also suggest a possible association of LZTR1 and RAS-GTPases with the autophagy. These findings provide clues for the elucidation of the mechanisms of RAS degradation and regulation of the RAS/MAPK signaling cascade.
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