RIT1 oncoproteins escape LZTR1-mediated proteolysis

Castel, Pau; Cheng, Anthony; Cuevas-Navarro, Antonio; Everman, David B.; Papageorge, Alex G.; Simanshu, Dhirendra K.; Tankka, Alexandra; Galeas, Jacqueline; Tlsty, Thea D.; McCormick, Frank

doi:10.1126/science.aav1444

Cited by 90 publications

(208 citation statements)

References 50 publications

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“…Castel et al recently reported that LZTR1 regulates polyubiquitination and degradation of RIT1 [39], supporting our finding that LZTR1 has a degradative effect on RAS-GTPases. RIT1 is a small GTPase, and mutations in RIT1 cause Noonan syndrome [14,40].…”

Section: Discussionsupporting

confidence: 92%

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LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases

et al. 2019

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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 K33linked 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 ubiquitinproteasome 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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Section: Discussionsupporting

confidence: 92%

“…S4). Castel et al showed that K135R and K187R double mutation abolished RIT1 degradation by LZTR1 [39]. RIT1-K135 coresponds to K117/K127 in four RAS-GTPases, while RIT1-K187 is located in HVR.…”

Section: Discussionmentioning

confidence: 99%

LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases

et al. 2019

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“…promoted the nonproteolytic ubiquitination of K, N, R-RAS and hyperactivate the RAS/MAPK signaling pathway (45,46). During our manuscript preparation, Castel et al also reported that LZTR1 regulates the ubiquitination and degradation of RIT1 (47). Although most of biochemical results from that paper, such as protein interaction, protein degradation, are consistent with our study, the biological importance of LZTR1-RIT1 axis dysregulation in glioblastoma was still unclear (47).…”

Section: Discussionsupporting

confidence: 81%

“…During our manuscript preparation, Castel et al also reported that LZTR1 regulates the ubiquitination and degradation of RIT1 (47). Although most of biochemical results from that paper, such as protein interaction, protein degradation, are consistent with our study, the biological importance of LZTR1-RIT1 axis dysregulation in glioblastoma was still unclear (47). Thus, these studies together with ours, suggested LZTR1 could suppress MAPK/ERK pathway activation through promoting the proteolytic or nonproteolytic ubiquitination of multiple components of this pathway.…”

Section: Discussionmentioning

confidence: 87%

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

Wang

Zhang

et al. 2020

Preprint

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Large-scale sequencing studies on glioblastoma have identified numerous genetic alterations.Leucine-zipper-like transcription regulator 1 (LZTR1) is inactivated by non-synonymous mutations and copy number losses, suggesting that it is a tumor suppressor in glioblastoma.However, how LZTR1 mutations contribute to glioblastoma pathogenesis remains poorly understood. Here, we revealed that LZTR1, as an adaptor of the CUL3 E3 ubiquitin ligase complex, recognizes and triggers ubiquitin-dependent degradation of oncoprotein RIT1, a RAS-like GTPase. Wild-type LZTR1 suppresses glioblastoma cell proliferation and migration by inactivating the MAPK/ERK signaling pathway in a RIT1-dependent manner. However, the effects were abrogated by the glioblastoma-associated LZTR1 mutations. Our findings revealed the underlying molecular mechanism of LZTR1 mutations-driven glioblastoma, and provide novel therapeutic target for LZTR1 mutations-driven glioblastoma.

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“…Three abstracts submitted by junior investigators were selected for platform presentation. Pau Castel recently showed that RIT1 is also a target of LZTR1-mediated ubiquitination (Castel et al, 2019). (Gripp et al, 2016;Ma et al, 2016).…”

Section: Novel Pathogenic Variants and Novel Genesmentioning

confidence: 99%

The sixth international RASopathies symposium: Precision medicine—From promise to practice

Gripp

Schill²,

Schoyer³

et al. 2019

American J of Med Genetics Pt A

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The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS‐mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life‐limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.

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RIT1 oncoproteins escape LZTR1-mediated proteolysis

Cited by 90 publications

References 50 publications

LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases

LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

The sixth international RASopathies symposium: Precision medicine—From promise to practice

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