title: KRAS insertion mutations are oncogenic and exhibit distinct functional properties.
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.
authors: Department of Pediatrics, University of California, 1450 3rd St, San Francisco, California 94158, USA.
authors: Yasmine
authors: Y
authors: White
authors: 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.|Van Andel Institute Graduate School, 333 Bostwick Ave N.E., Grand Rapids, Michigan 49503, USA.
authors: Aditi
authors: A
authors: Bagchi
authors: Department of Pathology, University of California, 2340 Sutter St, San Francisco, California 94115, USA.
authors: Jessica
authors: J
authors: Van Ziffle
authors: Department of Pediatrics, University of California, 1450 3rd St, San Francisco, California 94158, USA.
authors: Anagha
authors: A
authors: Inguva
authors: Plexxikon Inc, 91 Bolivar Dr, Berkeley, California 94710, USA.
authors: Gideon
authors: G
authors: Bollag
authors: Plexxikon Inc, 91 Bolivar Dr, Berkeley, California 94710, USA.
authors: Chao
authors: C
authors: Zhang
authors: Plexxikon Inc, 91 Bolivar Dr, Berkeley, California 94710, USA.
authors: Heidi
authors: H
authors: Carias
authors: 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.
authors: David
authors: D
authors: Dickens
authors: Department of Pediatrics, University of California, 1450 3rd St, San Francisco, California 94158, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, 1450 3rd St, San Francisco, California 94158, USA.
authors: Mignon
authors: M
authors: Loh
authors: Department of Pediatrics, University of California, 1450 3rd St, San Francisco, California 94158, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, 1450 3rd St, San Francisco, California 94158, USA.
authors: Kevin
authors: K
authors: Shannon
authors: Department of Pediatrics, University of California, 1450 3rd St, San Francisco, California 94158, USA.
authors: Ari J
authors: http://orcid.org/0000-0001-9902-443X
authors: AJ
authors: Firestone
mesh_terms: D000818:Animals; D002675:Child, Preschool; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D051379:Mice; D016254:Mutagenesis, Insertional; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D020080:Tandem Repeat Sequences; D014410:Tumor Stem Cell Assay
chemical_list: D020690:GTPase-Activating Proteins; C117307:KRAS protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras)