Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs
RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase...
Ausführliche Beschreibung
Autor*in: |
Antonio Cuevas-Navarro [verfasserIn] Laura Rodriguez-Muñoz [verfasserIn] Joaquim Grego-Bessa [verfasserIn] Alice Cheng [verfasserIn] Katherine A Rauen [verfasserIn] Anatoly Urisman [verfasserIn] Frank McCormick [verfasserIn] Gerardo Jimenez [verfasserIn] Pau Castel [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2022 |
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Übergeordnetes Werk: |
In: eLife - eLife Sciences Publications Ltd, 2013, 11(2022) |
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Übergeordnetes Werk: |
volume:11 ; year:2022 |
Links: |
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DOI / URN: |
10.7554/eLife.76495 |
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Katalog-ID: |
DOAJ084558261 |
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10.7554/eLife.76495 doi (DE-627)DOAJ084558261 (DE-599)DOAJ186607128fba49338544764486aeac28 DE-627 ger DE-627 rakwb eng QH301-705.5 Antonio Cuevas-Navarro verfasserin aut Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1. LZTR1 RIT1 noonan syndrome RASopathy CG3711 RIC Medicine R Science Q Biology (General) Laura Rodriguez-Muñoz verfasserin aut Joaquim Grego-Bessa verfasserin aut Alice Cheng verfasserin aut Katherine A Rauen verfasserin aut Anatoly Urisman verfasserin aut Frank McCormick verfasserin aut Gerardo Jimenez verfasserin aut Pau Castel verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.76495 kostenfrei https://doaj.org/article/186607128fba49338544764486aeac28 kostenfrei https://elifesciences.org/articles/76495 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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10.7554/eLife.76495 doi (DE-627)DOAJ084558261 (DE-599)DOAJ186607128fba49338544764486aeac28 DE-627 ger DE-627 rakwb eng QH301-705.5 Antonio Cuevas-Navarro verfasserin aut Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1. LZTR1 RIT1 noonan syndrome RASopathy CG3711 RIC Medicine R Science Q Biology (General) Laura Rodriguez-Muñoz verfasserin aut Joaquim Grego-Bessa verfasserin aut Alice Cheng verfasserin aut Katherine A Rauen verfasserin aut Anatoly Urisman verfasserin aut Frank McCormick verfasserin aut Gerardo Jimenez verfasserin aut Pau Castel verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.76495 kostenfrei https://doaj.org/article/186607128fba49338544764486aeac28 kostenfrei https://elifesciences.org/articles/76495 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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10.7554/eLife.76495 doi (DE-627)DOAJ084558261 (DE-599)DOAJ186607128fba49338544764486aeac28 DE-627 ger DE-627 rakwb eng QH301-705.5 Antonio Cuevas-Navarro verfasserin aut Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1. LZTR1 RIT1 noonan syndrome RASopathy CG3711 RIC Medicine R Science Q Biology (General) Laura Rodriguez-Muñoz verfasserin aut Joaquim Grego-Bessa verfasserin aut Alice Cheng verfasserin aut Katherine A Rauen verfasserin aut Anatoly Urisman verfasserin aut Frank McCormick verfasserin aut Gerardo Jimenez verfasserin aut Pau Castel verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.76495 kostenfrei https://doaj.org/article/186607128fba49338544764486aeac28 kostenfrei https://elifesciences.org/articles/76495 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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10.7554/eLife.76495 doi (DE-627)DOAJ084558261 (DE-599)DOAJ186607128fba49338544764486aeac28 DE-627 ger DE-627 rakwb eng QH301-705.5 Antonio Cuevas-Navarro verfasserin aut Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1. LZTR1 RIT1 noonan syndrome RASopathy CG3711 RIC Medicine R Science Q Biology (General) Laura Rodriguez-Muñoz verfasserin aut Joaquim Grego-Bessa verfasserin aut Alice Cheng verfasserin aut Katherine A Rauen verfasserin aut Anatoly Urisman verfasserin aut Frank McCormick verfasserin aut Gerardo Jimenez verfasserin aut Pau Castel verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.76495 kostenfrei https://doaj.org/article/186607128fba49338544764486aeac28 kostenfrei https://elifesciences.org/articles/76495 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs |
abstract |
RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1. |
abstractGer |
RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1. |
abstract_unstemmed |
RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1. |
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Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs |
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