Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor

Corina E Antal, Andrew M Hudson, Emily Kang, Ciro Zanca, Christopher Wirth, Natalie L Stephenson, Eleanor W Trotter, Lisa L Gallegos, Crispin J Miller, Frank B Furnari, Tony Hunter, John Brognard, Alexandra C Newton

Research output: Contribution to journalArticlepeer-review


Protein kinase C (PKC) isozymes have remained elusive cancer targets despite the unambiguous tumor promoting function of their potent ligands, phorbol esters, and the prevalence of their mutations. We analyzed 8% of PKC mutations identified in human cancers and found that, surprisingly, most were loss of function and none were activating. Loss-of-function mutations occurred in all PKC subgroups and impeded second-messenger binding, phosphorylation, or catalysis. Correction of a loss-of-function PKCβ mutation by CRISPR-mediated genome editing in a patient-derived colon cancer cell line suppressed anchorage-independent growth and reduced tumor growth in a xenograft model. Hemizygous deletion promoted anchorage-independent growth, revealing that PKCβ is haploinsufficient for tumor suppression. Several mutations were dominant negative, suppressing global PKC signaling output, and bioinformatic analysis suggested that PKC mutations cooperate with co-occurring mutations in cancer drivers. These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity.

Original languageEnglish
Pages (from-to)489-502
Number of pages14
Issue number3
Publication statusPublished - 29 Jan 2015


  • Animals
  • Cell Line, Tumor
  • Fluorescence Resonance Energy Transfer
  • Genes, Tumor Suppressor
  • Heterografts
  • Humans
  • Isoenzymes
  • Mice, Nude
  • Models, Molecular
  • Mutation
  • Neoplasm Transplantation
  • Neoplasms
  • Protein Kinase C
  • Protein Structure, Tertiary
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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