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Origin and Evolution of RAS Oncoprotein Membrane Targeting

KRAS, HRAS and NRAS oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS oncoproteins consist of a globular G-domain (aa1-166) and a 22-23aa unstructured hypervariable region (HVR) that mediates membrane...

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Autores principales: García-España, Antonio, Philips, Mark R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882654/
https://www.ncbi.nlm.nih.gov/pubmed/36711820
http://dx.doi.org/10.21203/rs.3.rs-2485219/v1
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author García-España, Antonio
Philips, Mark R.
author_facet García-España, Antonio
Philips, Mark R.
author_sort García-España, Antonio
collection PubMed
description KRAS, HRAS and NRAS oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS oncoproteins consist of a globular G-domain (aa1-166) and a 22-23aa unstructured hypervariable region (HVR) that mediates membrane targeting. The evolutionarily origins of the RAS isoforms, their HVRs and alternative splicing of the KRAS locus has not been explored. We found that KRAS is basal to the oncogene family and its duplication generated HRAS in the common ancestor of vertebrates. In a second round of duplication HRAS generated NRAS and KRAS generated an additional RAS gene we have designated KRASBL, absent in mammals and birds. KRAS4A arose through a duplication and insertion of the 4(th) exon of NRAS into the 3(rd) intron of KRAS. We found evolutionarily conservation of a short polybasic region (PBR1) in HRAS, NRAS and KRAS4A, a second polybasic region (PBR2) in KRAS4A, two neutralized basic residues (NB) and a serine in KRAS4B and KRASBL, and a modification of the CaaX motif in vertebrates with farnesyl rather than geranylgeranyl polyisoprene lipids, suggesting that a less hydrophobic membrane anchor is critical to RAS oncoprotein function. The persistence of four RAS isoforms through >400 MY of evolution argues strongly for differential function.
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spelling pubmed-98826542023-01-28 Origin and Evolution of RAS Oncoprotein Membrane Targeting García-España, Antonio Philips, Mark R. Res Sq Article KRAS, HRAS and NRAS oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS oncoproteins consist of a globular G-domain (aa1-166) and a 22-23aa unstructured hypervariable region (HVR) that mediates membrane targeting. The evolutionarily origins of the RAS isoforms, their HVRs and alternative splicing of the KRAS locus has not been explored. We found that KRAS is basal to the oncogene family and its duplication generated HRAS in the common ancestor of vertebrates. In a second round of duplication HRAS generated NRAS and KRAS generated an additional RAS gene we have designated KRASBL, absent in mammals and birds. KRAS4A arose through a duplication and insertion of the 4(th) exon of NRAS into the 3(rd) intron of KRAS. We found evolutionarily conservation of a short polybasic region (PBR1) in HRAS, NRAS and KRAS4A, a second polybasic region (PBR2) in KRAS4A, two neutralized basic residues (NB) and a serine in KRAS4B and KRASBL, and a modification of the CaaX motif in vertebrates with farnesyl rather than geranylgeranyl polyisoprene lipids, suggesting that a less hydrophobic membrane anchor is critical to RAS oncoprotein function. The persistence of four RAS isoforms through >400 MY of evolution argues strongly for differential function. American Journal Experts 2023-01-20 /pmc/articles/PMC9882654/ /pubmed/36711820 http://dx.doi.org/10.21203/rs.3.rs-2485219/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
García-España, Antonio
Philips, Mark R.
Origin and Evolution of RAS Oncoprotein Membrane Targeting
title Origin and Evolution of RAS Oncoprotein Membrane Targeting
title_full Origin and Evolution of RAS Oncoprotein Membrane Targeting
title_fullStr Origin and Evolution of RAS Oncoprotein Membrane Targeting
title_full_unstemmed Origin and Evolution of RAS Oncoprotein Membrane Targeting
title_short Origin and Evolution of RAS Oncoprotein Membrane Targeting
title_sort origin and evolution of ras oncoprotein membrane targeting
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882654/
https://www.ncbi.nlm.nih.gov/pubmed/36711820
http://dx.doi.org/10.21203/rs.3.rs-2485219/v1
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