An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma
Open Access
- 7 May 2019
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
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
Funding Information
- National Institutes of Health (2T32CA080416)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK121415)
- National Cancer Institute (R21CA177402)
- NIH Office of the Director (S10 OD021502)
- National Cancer Institute (R21CA201867)
- St. Baldrick's Foundation (Research Award)
- Fibrolamellar Cancer Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119192)
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