Inhibition of the chimeric DnaJ‐PKAc enzyme by endogenous inhibitor proteins

Citations Over Time

Abstract

The chimeric DnaJ-PKAc enzymeresulting from an approximately 400-kb deletion of chromosome 19 is a primary contributor to the oncogenic transformation that occurs in fibrolamellar hepatocellular carcinoma, also called fibrolamellar carcinoma (FLC). This oncogenic deletion juxtaposes exon 1 of the DNAJB1 heat shock protein gene with exon 2 of the PRKACA gene encoding the protein kinase A catalytic subunit, resulting in DnaJ-PKAc fusion under the transcriptional control of the DNAJB1 promoter. The expression of DnaJ-PKAc is approximately 10 times that of wild-type (wt) PKAc catalytic subunits, causing elevated and dysregulated kinase activity that contributes to oncogenic transformation. In normal cells, PKAc activity is regulated by a group of endogenous proteins, termed protein kinase inhibitors (PKI) that competitively inhibit PKAc and assist with the nuclear export of the enzyme. Currently, it is scarcely known whether interactions with PKI are perturbed in DnaJ-PKAc. In this report, we survey existing data sets to assess the expression levels of the various PKI isoforms that exist in humans to identify those that are candidates to encounter DnaJ-PKAc in both normal liver and FLC tumors. We then compare inhibition profiles of wtPKAc and DnaJ-PKAc against PKI and demonstrate that extensive structural homology in the active site clefts of the two enzymes confers similar kinase activities and inhibition by full-length PKI and PKI-derived peptides.

Related Papers

• → Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding(2000)615 cited
• → The α1 and α2 isoforms of the AMP‐activated protein kinase have similar activities in rat liver but exhibit differences in substrate specificity in vitro(1996)262 cited
• → AMP‐activated protein kinase isoenzyme family: subunit structure and chromosomal location(1997)117 cited
• → Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding(2000)96 cited
• → Cloning and Characterization of a New Member of the Family of Na+/K+-ATPase Genes(1994)