KRAS insertion mutations are oncogenic and exhibit distinct functional properties

Yasmine White; Aditi Bagchi; Jessica Van Ziffle; Anagha Inguva; Gideon Bollag; Chao Zhang; Heidi Carias; David Dickens; Mignon Loh; Kevin Shannon; Ari J Firestone

doi:10.1038/ncomms10647

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KRAS insertion mutations are oncogenic and exhibit distinct functional properties

Journal article

Open access

Peer reviewed

KRAS insertion mutations are oncogenic and exhibit distinct functional properties

Yasmine White, Aditi Bagchi, Jessica Van Ziffle, Anagha Inguva, Gideon Bollag, Chao Zhang, Heidi Carias, David Dickens, Mignon Loh, Kevin Shannon, …

Nature communications, Vol.7(1), pp.10647-10647

02/08/2016

DOI: 10.1038/ncomms10647

PMCID: PMC4748120

PMID: 26854029

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https://doi.org/10.1038/ncomms10647View

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Abstract

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.

Tumor Stem Cell Assay

Proto-Oncogene Proteins p21(ras) - genetics

Humans

Child, Preschool

Phosphatidylinositol 3-Kinases - metabolism

Tandem Repeat Sequences

GTPase-Activating Proteins - metabolism

Hepatocytes - metabolism

Animals

Mice

Mutagenesis, Insertional

Leukemia, Myelomonocytic, Juvenile - genetics

Mutation

Proto-Oncogene Proteins c-akt - metabolism

Details

Title: Subtitle: KRAS insertion mutations are oncogenic and exhibit distinct functional properties
Creators: Yasmine White - Department of Pediatrics, University of California, 1450 3rd St, San Francisco, California 94158, USA
Aditi Bagchi - Van Andel Institute Graduate School, 333 Bostwick Ave N.E., Grand Rapids, Michigan 49503, USA
Jessica Van Ziffle - Department of Pathology, University of California, 2340 Sutter St, San Francisco, California 94115, USA
Anagha Inguva - Department of Pediatrics, University of California, 1450 3rd St, San Francisco, California 94158, USA
Gideon Bollag - Plexxikon Inc, 91 Bolivar Dr, Berkeley, California 94710, USA
Chao Zhang - Plexxikon Inc, 91 Bolivar Dr, Berkeley, California 94710, USA
Heidi Carias - Plexxikon Inc, 91 Bolivar Dr, Berkeley, California 94710, USA
David Dickens - Department of Pediatrics, Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation; Helen DeVos Children's Hospital/Spectrum Health Medical Group, 100 Michigan St, Grand Rapids, Michigan 49503, USA
Mignon Loh - Helen Diller Family Comprehensive Cancer Center, University of California, 1450 3rd St, San Francisco, California 94158, USA
Kevin Shannon - Helen Diller Family Comprehensive Cancer Center, University of California, 1450 3rd St, San Francisco, California 94158, USA
Ari J Firestone - Department of Pediatrics, University of California, 1450 3rd St, San Francisco, California 94158, USA
Resource Type: Journal article
Publication Details: Nature communications, Vol.7(1), pp.10647-10647
DOI: 10.1038/ncomms10647
PMID: 26854029
PMCID: PMC4748120
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: R37CA72614 / NCI NIH HHS Howard Hughes Medical Institute R37 CA072614 / NCI NIH HHS
Language: English
Date published: 02/08/2016
Academic Unit: Stead Family Department of Pediatrics; Hematology/Oncology
Record Identifier: 9984093356902771

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