Prevalence of inactivating protein kinase C mutations in human cancers (1055.2)

Abstract

Protein kinase C (PKC) levels are aberrant in diverse cancers and over 400 mutations in PKC have been identified in human cancers. Here we characterized PKC mutations identified in human cancers to investigate whether PKCs function as oncogenes or tumor suppressors or whether their function is isozyme and/or context dependent. Live‐cell imaging was used to determine how these mutations affect PKC translocation, subcellular localization, and activity. Cell‐based assays were used to determine how PKC mutations alter proliferation, apoptosis, migration, and anchorage‐independent growth. Of 37 mutations we examined thus far, 24 of them reduced or completely abolished PKC activity, while only 1 increased it. These mutations reside within the diacylglycerol‐binding C1 domain, the Ca2+‐binding C2 domain, or the kinase domain of conventional, novel, or atypical PKCs. The inactivating mutations ablate activity by either impeding Ca2+ or diacylglycerol binding, or by yielding a misfolded kinase. Our results suggest that PKC can act as a tumor suppressor in certain cancers. Understanding whether mutations are activating or inactivating in specific cancers would allow us to determine whether therapeutic strategies should target ways to inactivate or activate PKC in the respective cancers.Grant Funding Source: This work was supported by GM43154 to ACN and DGE1144086 and T32 GM007752 to CEA.