Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor
Affiliations
- 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
Affiliations
- Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK
Affiliations
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
Affiliations
- Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA
Affiliations
- Applied Computational Biology and Bioinformatics Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK
Affiliations
- Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK
Affiliations
- Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK
Affiliations
- 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
Affiliations
- Applied Computational Biology and Bioinformatics Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK
Affiliations
- Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA
Affiliations
- Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK
Correspondence
- Corresponding author
Affiliations
- Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK
Correspondence
- Corresponding author
Affiliations
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
Correspondence
- Corresponding author
Affiliations
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
Correspondence
- Corresponding author
Article Info
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Highlights
- •Cancer-associated PKC mutations are LOF and can act in a dominant-negative manner
- •Correcting a heterozygous PKCβ LOF mutation reduces tumor volume
- •Hemizygous deletion shows PKC is haploinsufficient for tumor suppression
- •Therapeutic strategies should aim to restore PKC activity instead of inhibiting it
Summary
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.