Dataset Information

Mutation-specific and common phosphotyrosine signatures of KRAS G12D and G13D alleles

ABSTRACT: 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 and 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Colorectal Cancer

SUBMITTER: Akhilesh Pandey

LAB HEAD: Akhilesh Pandey, M.D, Ph.D.

PROVIDER: PXD009843 | Pride | 2021-06-09

REPOSITORIES: Pride

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Publications

Mutation-Specific and Common Phosphotyrosine Signatures of KRAS G12D and G13D Alleles.

Tahir Raiha R Renuse Santosh S Udainiya Savita S Madugundu Anil K AK Cutler Jevon A JA Nirujogi Raja Sekhar RS Na Chan Hyun CH Xu Yaoyu Y Wu Xinyan X Pandey Akhilesh A

Journal of proteome research 20201027 1

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 phosphotyrosi ...[more]

PMID: 32986951

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Project description:The small GTPase KRAS transmits signals from cell surface receptors to various downstream signaling pathways, thereby regulating a multitude of cellular processes. Activating KRAS mutations occur in approximately 30% of human cancers and contribute to malignant transformation through constitutive activation of downstream signaling cascades. These mutations cluster in several hotspots, with codons 12 and 13 being most commonly. It has been suggested that the position and type of amino acid exchange influence the transforming capacity of mutant KRAS proteins. To address this hypothesis, we used MCF10A human mammary epithelial cells to establish isogenic cell lines that express eight different cancer-associated KRAS mutations (G12C, G12D, G12V, G13C, G13D, A18D, Q61H, K117N) at physiological levels, and investigated the biochemical and functional consequences of the different KRAS variants in vitro. In addition, selected effects were evaluated in comparison to cells that overexpress mutant KRAS. The overall effects of mutants expressed at normal levels were moderate compared to overexpressed variants, but allowed delineation of biological functions that were related to specific alleles rather than KRAS expression level. None of the mutations induced morphological changes or migratory abilities. KRAS-G12D, -G12V, -G13D, and -K117N were able to mediate EGF-independent proliferation, whereas anchorage-independent growth was primarily induced by the K117N and Q61H variants. Analysis of known RAS effectors showed that none of the mutations led to increased phosphorylation of ERK, PDK1, or AKT. Both codon 13 mutations were associated with increased EGFR expression, which was not seen with other variants. Finally, comparative gene expression analysis of MCF10A-G13D versus MCF10A-G12D revealed distinct transcriptional changes, such as enhanced cytokine and p53 signaling, upon G13D expression. Together, we describe a useful resource for investigating the function of multiple KRAS mutations and provide insights into the differential effects of these variants in MCF10A cells.

Dataset Information

Mutation-specific and common phosphotyrosine signatures of KRAS G12D and G13D alleles

Publications

Mutation-Specific and Common Phosphotyrosine Signatures of <i>KRAS</i> G12D and G13D Alleles.

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