The protein kinase C(PKC) family has been intensely investigated in the context of cancer since the discovery that it is a receptor for the tumor-prompting phorbol esters. This led to the dogma that activation of PKC by phorbol esters promotes carcinogen-induced tumorigenesis, yet targeting PKC in cancer has been unsuccessful. There is the research team from UCSD trying to figure out the reason. Their study was published in Cell.

The PKC family contains nine genes that have many targets and thus diverse cellular functions, including cell survival, proliferation, apoptosis, and migration. PKC has proved an intractable target in cancer therapeutics and is frequently mutated in human cancers.

In this study, to uncover whether loss or gain of PKC function contributes to cancer progression, researchers selected mutations throughout the primary sequence and family membership and assessed their functional impact. Specifically, they asked how these cancer-associated mutations alter the signaling output of PKC using their genetically encoded reporter, C kinase activity reporter(CKAR). Characterization of 46 these mutations revealed that most reduced or abolished PKC activity and none were activating.

Bioinformatic analysis of all PKC mutations revealed genes and tumor suppressors known to be regulated by PKC. Their data are consistent with PKC isozymes functioning generally as tumor suppressors, reversing the paradigm that their hyperactivation promotes tumor growth.

Reference:

Antal C E, Hudson A M, Kang E, et al. Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor[J]. Cell, 2015.