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KRAS is one of the most frequently mutated genes across all cancer subtypes. Two of the most frequent oncogenic KRAS mutations observed in patients result in glycine to aspartic acid substitution at either codon 12 (G12D) or 13 (G13D). Although the biochemical differences between these two predominant mutations are not fully understood, distinct clinical features of the resulting tumors suggest involvement of disparate signaling mechanisms. When we compared the global phosphotyrosine proteomic profiles of isogenic colorectal cancer cell lines bearing either G12D or G13D KRAS mutation, we observed both shared as well as unique signaling events induced by the two KRAS mutations. Remarkably, while the G12D mutation led to an increase in membrane proximal and adherens junction signaling, the G13D mutation led to activation of signaling molecules such as nonreceptor tyrosine kinases, MAPK kinases, and regulators of metabolic processes. The importance of one of the cell surface molecules, MPZL1, which was found to be hyperphosphorylated in G12D cells, was confirmed by cellular assays as its knockdown led to a decrease in proliferation of G12D but not G13D expressing cells. Overall, our study reveals important signaling differences across two common KRAS mutations and highlights the utility of our approach to systematically dissect subtle differences between related oncogenic mutants and potentially lead to individualized treatments.

Xianshuo Zhang,a Peipei Wang,a Yaoyu Xu,a Jun Wang,b Yunfeng Shi,a,* Wenxu Niu,a Wenjing Song,a Ruru Liu,a Cui-yun Yu,b and Hua Weib,* Facile synthesis of amphiphilic hyperbranched copolymers with biodegradability generally...

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A Tag-Sec fluorescent probe was designed that could detect both thioredoxin reductase and selenocysteine with high sensitivity, selectivity, broad pH tolerance and good water solubility.

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Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, which usually presents at a late stage and has a poor prognosis. Thus, there is an urge need for...