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Increased activity of protein kinase A, even without DNAJB1, is sufficient to cause Fibrolamellar hepatocellular carcinoma

ABSTRACT: Most fibrolamellar carcinoma (FLC) is driven by a fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA holoenzyme activity is controlled through a regulatory protein (R) that both inhibits and localizes catalytic activity. An excess of regulatory subunits ensures PRKACA activity is normally inhibited. In FLC patient tumors driven by DNAJB1::PRKACA we find an increase in the ratio of catalytic to regulatory units by mass spectrometry, biochemistry and immunofluorescence, with increased kinase in the nucleus. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes of primary human hepatocytes; these recapitulated most changes observed in FLC. This is consistent with the observation that FLC is found in patients missing a regulatory subunit or with a ATP1B1::PRKACA fusion. Thus, the DNAJB1 domain is not required for FLC. Instead, changes in PKA quantity and localization determine the FLC phenotype.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Soren Heissel

LAB HEAD: Sanford M. Simon

PROVIDER: PXD043816 | Pride | 2024-05-17

REPOSITORIES: Pride

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