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

Authors
  • Ce, Antal
  • Am, Hudson
  • E, Kang
  • C, Zanca
  • C, Wirth
  • Nl, Stephenson
  • Ew, Trotter
  • Ll, Gallegos
  • Cj, Miller
  • Fb, Furnari
  • Tony Hunter
  • J, Brognard
  • Ac, Newton
Type
Published Article
Journal
Cell
Publisher
Elsevier
Volume
160
Issue
3
Pages
489–502
Identifiers
DOI: 10.1016/j.cell.2015.01.001
Source
Hunter Lab
License
Unknown

Abstract

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.

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