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

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

Author information

1
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA.
2
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
3
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
4
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
5
Applied Computational Biology and Bioinformatics Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
6
The Salk Institute, La Jolla, CA 92037, USA.
7
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK. Electronic address: john.brognard@cruk.manchester.ac.uk.
8
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: anewton@ucsd.edu.

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.

PMID:
25619690
PMCID:
PMC4313737
DOI:
10.1016/j.cell.2015.01.001
[Indexed for MEDLINE]
Free PMC Article

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