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KRAS insertion mutations are oncogenic and exhibit distinct functional properties
Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). Here we discover a partial duplication of the switch 2 domain of K-Ras encoding a tandem repeat of amino acids G60_A66dup in a ch...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748120/ https://www.ncbi.nlm.nih.gov/pubmed/26854029 http://dx.doi.org/10.1038/ncomms10647 |
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author | White, Yasmine Bagchi, Aditi Van Ziffle, Jessica Inguva, Anagha Bollag, Gideon Zhang, Chao Carias, Heidi Dickens, David Loh, Mignon Shannon, Kevin Firestone, Ari J. |
author_facet | White, Yasmine Bagchi, Aditi Van Ziffle, Jessica Inguva, Anagha Bollag, Gideon Zhang, Chao Carias, Heidi Dickens, David Loh, Mignon Shannon, Kevin Firestone, Ari J. |
author_sort | White, Yasmine |
collection | PubMed |
description | Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). Here we discover a partial duplication of the switch 2 domain of K-Ras encoding a tandem repeat of amino acids G60_A66dup in a child with an atypical myeloproliferative neoplasm. K-Ras proteins containing this tandem duplication or a similar five amino acid E62_A66dup mutation identified in lung and colon cancers transform the growth of primary myeloid progenitors and of Ba/F3 cells. Recombinant K-Ras(G60_A66dup) and K-Ras(E62_A66dup) proteins display reduced intrinsic GTP hydrolysis rates, accumulate in the GTP-bound conformation and are resistant to GAP-mediated GTP hydrolysis. Remarkably, K-Ras proteins with switch 2 insertions are impaired for PI3 kinase binding and Akt activation, and are hypersensitive to MEK inhibition. These studies illuminate a new class of oncogenic KRAS mutations and reveal unexpected plasticity in oncogenic Ras proteins that has diagnostic and therapeutic implications. |
format | Online Article Text |
id | pubmed-4748120 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47481202016-02-24 KRAS insertion mutations are oncogenic and exhibit distinct functional properties White, Yasmine Bagchi, Aditi Van Ziffle, Jessica Inguva, Anagha Bollag, Gideon Zhang, Chao Carias, Heidi Dickens, David Loh, Mignon Shannon, Kevin Firestone, Ari J. Nat Commun Article Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). Here we discover a partial duplication of the switch 2 domain of K-Ras encoding a tandem repeat of amino acids G60_A66dup in a child with an atypical myeloproliferative neoplasm. K-Ras proteins containing this tandem duplication or a similar five amino acid E62_A66dup mutation identified in lung and colon cancers transform the growth of primary myeloid progenitors and of Ba/F3 cells. Recombinant K-Ras(G60_A66dup) and K-Ras(E62_A66dup) proteins display reduced intrinsic GTP hydrolysis rates, accumulate in the GTP-bound conformation and are resistant to GAP-mediated GTP hydrolysis. Remarkably, K-Ras proteins with switch 2 insertions are impaired for PI3 kinase binding and Akt activation, and are hypersensitive to MEK inhibition. These studies illuminate a new class of oncogenic KRAS mutations and reveal unexpected plasticity in oncogenic Ras proteins that has diagnostic and therapeutic implications. Nature Publishing Group 2016-02-08 /pmc/articles/PMC4748120/ /pubmed/26854029 http://dx.doi.org/10.1038/ncomms10647 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article White, Yasmine Bagchi, Aditi Van Ziffle, Jessica Inguva, Anagha Bollag, Gideon Zhang, Chao Carias, Heidi Dickens, David Loh, Mignon Shannon, Kevin Firestone, Ari J. KRAS insertion mutations are oncogenic and exhibit distinct functional properties |
title | KRAS insertion mutations are oncogenic and exhibit distinct functional properties |
title_full | KRAS insertion mutations are oncogenic and exhibit distinct functional properties |
title_fullStr | KRAS insertion mutations are oncogenic and exhibit distinct functional properties |
title_full_unstemmed | KRAS insertion mutations are oncogenic and exhibit distinct functional properties |
title_short | KRAS insertion mutations are oncogenic and exhibit distinct functional properties |
title_sort | kras insertion mutations are oncogenic and exhibit distinct functional properties |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748120/ https://www.ncbi.nlm.nih.gov/pubmed/26854029 http://dx.doi.org/10.1038/ncomms10647 |
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