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.