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.
journal_name
Celljournal_title
Cellauthors
Antal CE,Hudson AM,Kang E,Zanca C,Wirth C,Stephenson NL,Trotter EW,Gallegos LL,Miller CJ,Furnari FB,Hunter T,Brognard J,Newton ACdoi
10.1016/j.cell.2015.01.001subject
Has Abstractpub_date
2015-01-29 00:00:00pages
489-502issue
3eissn
0092-8674issn
1097-4172pii
S0092-8674(15)00002-1journal_volume
160pub_type
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