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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-RasG60_A66dup and K-RasE62_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.
Highlights
Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs)
Taken together with the highly conserved nature of the Ras/GAP switch, the amino acid substitutions identified in cancer and Noonan syndrome suggest that a limited spectrum of mutations are capable of causing disease by constitutively activating Ras output
K-RasG60_A66dup and K-RasE62_A66dup are the first oncogenic Ras proteins with strong selectivity for Raf versus phosphatidylinositol 3-kinase (PI3K) binding. This is unexpected given the large body of data implicating activation of both Raf/MEK/ERK and PI3K/Akt signalling downstream of oncogenic K-Ras as essential in Juvenile myelomonocytic leukaemia (JMML) and lung cancer pathogenesis
Summary
Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). KRAS codons 12, 13 and 61 are the most common foci of dominant oncogenic mutations in human cancer[4,5] Substitutions in these residues result in constitutively elevated levels of Ras-GTP due to reduced intrinsic GTP hydrolysis and resistance to GAPs2–4. We describe insertion mutations within the switch 2 domain of KRAS that potently inhibit K-Ras intrinsic and GAP-mediated GTP hydrolysis. These mutations result in elevated MAPK signalling, but are defective in stimulating PI3K activity. Cells transformed by these mutations show heightened sensitivity to growth inhibition by MEK inhibitors suggesting a therapeutic potential for the treatment of disease harbouring these or similar mutations
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