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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...

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Autores principales: White, Yasmine, Bagchi, Aditi, Van Ziffle, Jessica, Inguva, Anagha, Bollag, Gideon, Zhang, Chao, Carias, Heidi, Dickens, David, Loh, Mignon, Shannon, Kevin, Firestone, Ari J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
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.
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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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