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

Cell. 2015 Jan 29;160(3):489-502. doi: 10.1016/j.cell.2015.01.001. Epub 2015 Jan 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Fluorescence Resonance Energy Transfer
  • Genes, Tumor Suppressor
  • Heterografts
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mice, Nude
  • Models, Molecular
  • Mutation
  • Neoplasm Transplantation
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Protein Kinase C / chemistry*
  • Protein Kinase C / genetics*
  • Protein Kinase C / metabolism
  • Protein Structure, Tertiary


  • Isoenzymes
  • Protein Kinase C