Protein kinase C fusion proteins are paradoxically loss-of-function in cancer

An-Angela N. Van, Maya T. Kunkel, Timothy R. Baffi, Gema Lordén, Corina E. Antal, Sourav Banerjee, Alexandra C. Newton (Lead / Corresponding author)

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Abstract

Within the AGC kinase superfamily, gene fusions resulting from chromosomal rearrangements have been most frequently described for protein kinase C (PKC), with gene fragments encoding either the C-terminal catalytic domain or the N-terminal regulatory moiety fused to other genes. Kinase fusions that eliminate regulatory domains are typically gain-of-function and often oncogenic. However, several quality control pathways prevent accumulation of aberrant PKC, suggesting that PKC fusions may paradoxically be loss-of-function. To explore this topic, we used biochemical, cellular, and genome editing approaches to investigate the function of fusions that retain the portion of the gene encoding either the catalytic domain or regulatory domain of PKC. Overexpression studies revealed that PKC catalytic domain fusions were constitutively active but vulnerable to degradation. Genome editing of endogenous genes to generate a cancer-associated PKC fusion resulted in cells with detectable levels of fusion transcript but no detectable protein. Hence, PKC catalytic domain fusions are paradoxically loss-of-function as a result of their instability, preventing appreciable accumulation of protein in cells. Overexpression of a PKC regulatory domain fusion suppressed both basal and agonist-induced endogenous PKC activity, acting in a dominant-negative manner by competing for diacylglycerol. For both catalytic and regulatory domain fusions, the PKC component of the fusion proteins mediated the effects of the full-length fusions on the parameters examined, suggesting that the partner protein is dispensable in these contexts. Taken together, our findings reveal that PKC gene fusions are distinct from oncogenic fusions and present a mechanism by which loss of PKC function occurs in cancer.
Original languageEnglish
Article number100445
Pages (from-to)1-18
Number of pages18
JournalJournal of Biological Chemistry
Volume296
Early online date20 Feb 2021
DOIs
Publication statusE-pub ahead of print - 20 Feb 2021

Keywords

  • protein kinase C (PKC)
  • gene fusions
  • cancer
  • catalytic domain
  • loss-of-function
  • autoinhibition
  • constitutively active
  • protein degradation
  • regulatory domain
  • dominant negative

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