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Mutation-Specific and Common Phosphotyrosine Signatures of KRASG12D and G13D Alleles

Mutation-Specific and Common Phosphotyrosine Signatures of KRASG12D and G13D Alleles

Authors :
Tahir, Raiha
Renuse, Santosh
Udainiya, Savita
Madugundu, Anil K.
Cutler, Jevon A.
Nirujogi, Raja Sekhar
Na, Chan Hyun
Xu, Yaoyu
Wu, Xinyan
Pandey, Akhilesh
Source :
Journal of Proteome Research; January 2021, Vol. 20 Issue: 1 p670-683, 14p
Publication Year :
2021

Abstract

KRASis one of the most frequently mutated genes across all cancer subtypes. Two of the most frequent oncogenic KRASmutations 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 KRASmutation, we observed both shared as well as unique signaling events induced by the two KRASmutations. 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 KRASmutations and highlights the utility of our approach to systematically dissect subtle differences between related oncogenic mutants and potentially lead to individualized treatments.

Details

Language :
English
ISSN :
15353893 and 15353907
Volume :
20
Issue :
1
Database :
Supplemental Index
Journal :
Journal of Proteome Research
Publication Type :
Periodical
Accession number :
ejs54300869
Full Text :
https://doi.org/10.1021/acs.jproteome.0c00587