An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma
- University of Washington Medical Center, United States
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.
Data availability
There are no restrictions to the availability of our data. Raw mass spectrometry data has been uploaded to MassIVE, an NIH supported MS data repository (MSV000083167). Data will be made publicly available.
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An acquired scaffolding function of the DNAJ-PKAc fusion enhances oncogenesis in Fibrolamellar carcinomaMassIVE Repository, doi:10.25345/C5F01X.
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.
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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An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma
eLife 8:e44187.
https://doi.org/10.7554/eLife.44187
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