An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma

Elife. 2019 May 7;8:e44187. doi: 10.7554/eLife.44187.

Abstract

Fibrolamellar carcinoma (FLC) is a rare liver cancer. FLCs uniquely produce DNAJ-PKAc, a chimeric enzyme consisting of a chaperonin-binding domain fused to the Cα subunit of protein kinase A. Biochemical analyses of clinical samples reveal that a unique property of this fusion enzyme is the ability to recruit heat shock protein 70 (Hsp70). This cellular chaperonin is frequently up-regulated in cancers. Gene-editing of mouse hepatocytes generated disease-relevant AML12DNAJ-PKAc cell lines. Further analyses indicate that the proto-oncogene A-kinase anchoring protein-Lbc is up-regulated in FLC and functions to cluster DNAJ-PKAc/Hsp70 sub-complexes with a RAF-MEK-ERK kinase module. Drug screening reveals Hsp70 and MEK inhibitor combinations that selectively block proliferation of AML12DNAJ-PKAc cells. Phosphoproteomic profiling demonstrates that DNAJ-PKAc biases the signaling landscape toward ERK activation and engages downstream kinase cascades. Thus, the oncogenic action of DNAJ-PKAc involves an acquired scaffolding function that permits recruitment of Hsp70 and mobilization of local ERK signaling.

Keywords: MAP kinase; Protein kinase A; biochemistry; cancer biology; chemical biology; combination therapy; fibrolamellar carcinoma; human; intratumoral heterogeneity; local signaling; mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / metabolism
  • Animals
  • Carcinoma, Hepatocellular / physiopathology*
  • Cell Line
  • Cell Proliferation
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / metabolism*
  • Fetal Proteins / genetics
  • Fetal Proteins / metabolism*
  • HSP70 Heat-Shock Proteins / metabolism
  • Hepatocytes / pathology
  • Humans
  • Liver Neoplasms / physiopathology*
  • Mice
  • Models, Theoretical
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Protein Binding
  • Proto-Oncogene Mas
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Signal Transduction

Substances

  • A Kinase Anchor Proteins
  • DNAJC14 protein, human
  • Fetal Proteins
  • HSP70 Heat-Shock Proteins
  • MAS1 protein, human
  • Molecular Chaperones
  • Proto-Oncogene Mas
  • Recombinant Fusion Proteins
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • protein kinase A Calpha

Supplementary concepts

  • Fibrolamellar hepatocellular carcinoma