Cargando…
A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions
Active mutations in the RAS genes are found in ∼30% of human cancers. Although thought to have overlapping functions, RAS isoforms show preferential activation in human tumors, which prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific and nucleotide-...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9396065/ https://www.ncbi.nlm.nih.gov/pubmed/35839996 http://dx.doi.org/10.1016/j.mcpro.2022.100268 |
_version_ | 1784771846203244544 |
---|---|
author | Miller, Seth P. Maio, George Zhang, Xiaoyu Badillo Soto, Felix S. Zhu, Julia Ramirez, Stephen Z. Lin, Hening |
author_facet | Miller, Seth P. Maio, George Zhang, Xiaoyu Badillo Soto, Felix S. Zhu, Julia Ramirez, Stephen Z. Lin, Hening |
author_sort | Miller, Seth P. |
collection | PubMed |
description | Active mutations in the RAS genes are found in ∼30% of human cancers. Although thought to have overlapping functions, RAS isoforms show preferential activation in human tumors, which prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific and nucleotide-dependent interactomes of the four RAS isoforms, KRAS4A, KRAS4B, HRAS, and NRAS. Many isoform-specific interacting proteins were identified, including HRAS-specific CARM1 and CHK1 and KRAS-specific PIP4K2C and IPO7. Comparing the interactomes of WT and constitutively active G12D mutant of RAS isoforms, we identified several potential previously unknown effector proteins of RAS, one of which was recently reported while this article was in preparation, RADIL. These interacting proteins play important roles as knockdown or pharmacological inhibition leads to potent inhibition of cancer cells. The HRAS-specific interacting protein CARM1 plays a role in HRAS-induced senescence, with CARM1 knockdown or inhibition selectively increasing senescence in HRAS-transformed cells but not in KRAS4B-transformed cells. By revealing new isoform-specific and nucleotide-dependent RAS interactors, the study here provides insights to help understand the overlapping functions of the RAS isoforms. |
format | Online Article Text |
id | pubmed-9396065 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-93960652022-08-25 A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions Miller, Seth P. Maio, George Zhang, Xiaoyu Badillo Soto, Felix S. Zhu, Julia Ramirez, Stephen Z. Lin, Hening Mol Cell Proteomics Research Active mutations in the RAS genes are found in ∼30% of human cancers. Although thought to have overlapping functions, RAS isoforms show preferential activation in human tumors, which prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific and nucleotide-dependent interactomes of the four RAS isoforms, KRAS4A, KRAS4B, HRAS, and NRAS. Many isoform-specific interacting proteins were identified, including HRAS-specific CARM1 and CHK1 and KRAS-specific PIP4K2C and IPO7. Comparing the interactomes of WT and constitutively active G12D mutant of RAS isoforms, we identified several potential previously unknown effector proteins of RAS, one of which was recently reported while this article was in preparation, RADIL. These interacting proteins play important roles as knockdown or pharmacological inhibition leads to potent inhibition of cancer cells. The HRAS-specific interacting protein CARM1 plays a role in HRAS-induced senescence, with CARM1 knockdown or inhibition selectively increasing senescence in HRAS-transformed cells but not in KRAS4B-transformed cells. By revealing new isoform-specific and nucleotide-dependent RAS interactors, the study here provides insights to help understand the overlapping functions of the RAS isoforms. American Society for Biochemistry and Molecular Biology 2022-07-14 /pmc/articles/PMC9396065/ /pubmed/35839996 http://dx.doi.org/10.1016/j.mcpro.2022.100268 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Miller, Seth P. Maio, George Zhang, Xiaoyu Badillo Soto, Felix S. Zhu, Julia Ramirez, Stephen Z. Lin, Hening A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions |
title | A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions |
title_full | A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions |
title_fullStr | A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions |
title_full_unstemmed | A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions |
title_short | A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions |
title_sort | proteomic approach identifies isoform-specific and nucleotide-dependent ras interactions |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9396065/ https://www.ncbi.nlm.nih.gov/pubmed/35839996 http://dx.doi.org/10.1016/j.mcpro.2022.100268 |
work_keys_str_mv | AT millersethp aproteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT maiogeorge aproteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT zhangxiaoyu aproteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT badillosotofelixs aproteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT zhujulia aproteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT ramirezstephenz aproteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT linhening aproteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT millersethp proteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT maiogeorge proteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT zhangxiaoyu proteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT badillosotofelixs proteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT zhujulia proteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT ramirezstephenz proteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions AT linhening proteomicapproachidentifiesisoformspecificandnucleotidedependentrasinteractions |