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Cancer‐Associated Fusion Proteins Reveal Inhibitory Role of Protein Kinase C's Processing Phosphorylations
Author(s) -
Baffi Timothy R.,
Ngoc Van AnAngela,
Antal Corina E.,
Newton Alexandra C.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1115.5
Subject(s) - protein kinase c , fusion protein , biology , phosphorylation , fusion gene , cancer , microbiology and biotechnology , kinase , signal transduction , chronic myelogenous leukemia , cancer research , gene , biochemistry , leukemia , genetics , recombinant dna
Since the discovery that the Philadelphia translocation event produces the oncogenic Bcr‐Abl fusion gene that sustains chronic myelogenous leukemia (CML), gain‐of‐function fusion proteins have emerged as novel cancer drivers and potential therapeutic targets. Recently, several fusion proteins involving translocations in the N‐terminal regulatory region of the tumor suppressor Protein Kinase C (PKC) were identified in cancer. Here, we show that the fusion proteins are not processed by phosphorylation, an event that accompanies the maturation of wild‐type PKC, yet are, surprisingly, constitutively and maximally active, independent of membrane‐targeting second messengers. This constitutive activity is not a result of the various proteins to which PKC is fused, but instead results from deletion of the autoinhibitory pseudosubstrate in the fusion protein: constructs of PKC deleted in just the pseudosubstrate are also not phosphorylated yet constitutively and maximally active in cells. Because unphosphorylated PKC is unstable and sensitive to degradation, it is not clear whether these fusion proteins exist in appreciable levels in the tumors in which their mRNA was identified. Importantly, however, characterization of these fusions reveals the unexpected finding that phosphorylation serves as a mechanism to maintain it in an autoinhibited state. Characterizing the functional consequences of fusion proteins in cancer is not only critical to understanding their contribution to oncogenic signaling, but also to elucidating the underlying biochemical regulatory mechanisms of relevant enzymes such as PKC. Support or Funding Information This work was supported by the National Institutes of Health Grant GM43154 and the UCSD Graduate Training Program in Cellular and Molecular Pharmacology (T32 GM007752).