D154Q Mutation does not Alter KRAS Dimerization

Ingrid Grozavu; Sarah Stuart; Anna Lyakisheva; Zhong Yao; Shivanthy Pathmanathan; Michael Ohh; Igor Stagljar

doi:10.1016/j.jmb.2021.167392

D154Q Mutation does not Alter KRAS Dimerization

J Mol Biol. 2022 Jan 30;434(2):167392. doi: 10.1016/j.jmb.2021.167392. Epub 2021 Dec 10.

Authors

Ingrid Grozavu¹, Sarah Stuart², Anna Lyakisheva¹, Zhong Yao¹, Shivanthy Pathmanathan³, Michael Ohh², Igor Stagljar⁴

Affiliations

¹ Donnelly Centre, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
² Department of Biochemistry, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³ Donnelly Centre, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁴ Donnelly Centre, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Mediterranean Institute for Life Sciences (MedILS), Split, Croatia; School of Medicine, University of Split, Croatia. Electronic address: igor.stagljar@utoronto.ca.

PMID: 34896362
DOI: 10.1016/j.jmb.2021.167392

Abstract

KRAS is one of the most frequently mutated oncogenes in human cancers. Despite nearly 40 years of research, KRAS remains largely undruggable, in part due to an incomplete understanding of its biology. Recently, KRAS dimerization was discovered to play an important role in its signalling function. The KRAS D154Q mutant was described as a dimer-deficient variant that can be used to study the effect of dimerization in KRAS oncogenicity. However, we show here that KRAS D154Q homo- and heterodimerized with KRAS WT using three separate protein-protein interaction assays, and that oncogenic KRAS dimerization was not negatively impacted by the presence of a secondary D154Q mutation. In conclusion, we advise caution in using this variant to study the purpose of dimerization in KRAS oncogenic behaviour.

Keywords: Cancer therapeutics; KRAS; MaMTH; Oncogenic signalling; SIMPL; co-immunoprecipitation; dimerization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Dimerization
Humans
Immunoprecipitation
Mutation*
Neoplasms / therapy
Proto-Oncogene Proteins p21(ras) / chemistry*
Proto-Oncogene Proteins p21(ras) / genetics*
Signal Transduction

Substances

KRAS protein, human
Proto-Oncogene Proteins p21(ras)

Grants and funding

420989/CIHR/Canada