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

• DOI: 10.7554/elife.44187
• Publication Date: 2019-05-07T12:00:30Z
• Authors: Rigney E Turnham; F Donelson Smith; Heidi L Kenerson; Mitchell H Omar; Martin Golkowski; Irvin Garcia; Renay Bauer; Ho-Tak Lau; Kevin M Sullivan; Lorene K Langeberg; Shao-En Ong; Kimberly J Riehle; Raymond S Yeung; John D Scott
• Keywords: Fetal Proteins; 0301 basic medicine; Carcinoma, Hepatocellular; QH301-705.5; Science; Recombinant Fusion Proteins; A Kinase Anchor Proteins; Proto-Oncogene Mas; combination therapy; Cell Line; Mice; 03 medical and health sciences; Protein kinase A; Biochemistry and Chemical Biology; local signaling; Animals; Humans; HSP70 Heat-Shock Proteins; Biology (General); Cell Proliferation; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; Q; Liver Neoplasms; R; Models, Theoretical; 3. Good health; intratumoral heterogeneity; Hepatocytes; Medicine; MAP kinase; fibrolamellar carcinoma; Molecular Chaperones; Protein Binding; Signal Transduction

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.