Research ArticleCancer

Cancer-associated arginine-to-histidine mutations confer a gain in pH sensing to mutant proteins

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Sci. Signal.  05 Sep 2017:
Vol. 10, Issue 495, eaam9931
DOI: 10.1126/scisignal.aam9931

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Cancer’s pH-sensitive mutants

Mutations that change an arginine residue to a histidine residue (Arg-to-His) in various proteins are associated with cancer. Given that histidine residues are critical in proteins that respond to changes in pH, White et al. looked at two proteins that frequently have Arg-to-His mutations in tumors and found that a rise in intracellular pH conferred these mutants with oncogenic effects. Molecular modeling of the growth factor receptor EGFR suggested that the mutation stabilizes the kinase in an active conformation, but only when the cells have a high pH. An Arg-to-His mutation in the transcription factor and tumor suppressor p53 inhibited its activity when intracellular pH was high. Thus, decreasing pH in tumor cells might be a way to target EGFR or reactivate p53, which has been difficult to treat durably or effectively in cancer patients.

Abstract

The intracellular pH (pHi) of most cancers is constitutively higher than that of normal cells and enhances proliferation and cell survival. We found that increased pHi enabled the tumorigenic behaviors caused by somatic arginine-to-histidine mutations, which are frequent in cancer and confer pH sensing not seen with wild-type proteins. Experimentally raising the pHi increased the activity of R776H mutant epidermal growth factor receptor (EGFR-R776H), thereby increasing proliferation and causing transformation in fibroblasts. An Arg-to-Gly mutation did not confer these effects. Molecular dynamics simulations of EGFR suggested that decreased protonation of His776 at high pH causes conformational changes in the αC helix that may stabilize the active form of the kinase. An Arg-to-His, but not Arg-to-Lys, mutation in the transcription factor p53 (p53-R273H) decreased its transcriptional activity and attenuated the DNA damage response in fibroblasts and breast cancer cells with high pHi. Lowering pHi attenuated the tumorigenic effects of both EGFR-R776H and p53-R273H. Our data suggest that some somatic mutations may confer a fitness advantage to the higher pHi of cancer cells.

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