MassIVE MSV000083167

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An acquired scaffolding function of the DNAJ-PKAc fusion enhances oncogenesis in Fibrolamellar carcinoma

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Description

Fibrolamellar carcinoma (FLC) is a rare liver cancer. FLC tumors exclusively produce DNAJ-PKAc, a de novo chimeric enzyme consisting of a chaperonin-binding domain fused to the C subunit of protein kinase A. Biochemical analyses of clinical samples reveal that a unique property of DNAJ-PKAc 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. Drug-screening discovered Hsp70 and MEK inhibitor combinations that selectively block proliferation of AML12DNAJ-PKAc cells. Further analyses indicate that the proto-oncogene AKAP-Lbc is upregulated in FLC and functions to cluster DNAJ-PKAc/Hsp70 sub-complexes with a RAF-MEK-ERK kinase module. Phosphoproteomic profiling infers that DNAJ-PKAc biases the signaling landscape toward ERK activation and mobilizes other downstream kinase cascades. We propose that the oncogenic nature of DNAJ-PKAc proceeds through an acquired scaffolding function that permits recruitment of Hsp70 and stabilizes ERK signaling. [doi:10.25345/C5F01X] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Fibrolamellar carcinoma, Protein kinase A, Phosphoproteomics

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Principal Investigators:
(in alphabetical order) 		John D. Scott, University of Washington, Department of Pharmacology, United States
Submitting User: golkom
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