An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma
- University of Washington Medical Center, United States
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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 Ca 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.
Article and author information
Author details
Lorene K Langeberg
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119192)
- John D Scott
Fibrolamellar Cancer Foundation
- John D Scott
National Cancer Institute (R21CA201867)
- Kimberly J Riehle
St. Baldrick's Foundation
- Kimberly J Riehle
National Cancer Institute (R21CA177402)
- Shao-En Ong
NIH Office of the Director (S10 OD021502)
- Shao-En Ong
National Institutes of Health (2T32CA080416)
- Rigney E Turnham
National Institute of Diabetes and Digestive and Kidney Diseases (F32DK121415)
- Mitchell H Omar
Fibrolamellar Cancer Foundation
- Raymond S Yeung
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Roger J Davis, University of Massachusetts Medical School, United States
Publication history
- Received: December 6, 2018
- Accepted: May 5, 2019
- Accepted Manuscript published: May 7, 2019 (version 1)
- Version of Record published: May 23, 2019 (version 2)
Copyright
© 2019, Turnham et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Biochemistry and Chemical Biology
- Cell Biology
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- Biochemistry and Chemical Biology
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