title: Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor.
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.
authors.affiliation: 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.
authors.forename: Corina E
authors.initials: CE
authors.lastname: Antal
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hudson
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Kang
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Ciro
authors.initials: C
authors.lastname: Zanca
authors.affiliation: Applied Computational Biology and Bioinformatics Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wirth
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Stephenson
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Eleanor W
authors.initials: EW
authors.lastname: Trotter
authors.affiliation: 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.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Gallegos
authors.affiliation: Applied Computational Biology and Bioinformatics Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Crispin J
authors.initials: CJ
authors.lastname: Miller
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.affiliation: The Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Brognard
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: anewton@ucsd.edu.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D031541:Fluorescence Resonance Energy Transfer; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D008958:Models, Molecular; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D011493:Protein Kinase C / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C