Proteomics

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


ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion, LTQ Orbitrap Elite

SUBMITTER: John D. Scott  

PROVIDER: MSV000083167 | MassIVE | Tue Nov 27 11:15:00 GMT 2018

REPOSITORIES: MassIVE

Dataset's files

Source:
Action DRS
MSV000083167 Other
params.xml Xml
20160202_FLC_7-9_NAL-1.mzML Mzml
20160202_FLC_7-9_NAL-2.mzML Mzml
20160202_FLC_7-9_NAL-3.mzML Mzml
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