An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma.
Rigney E TurnhamF Donelson SmithHeidi L KenersonMitchell H OmarMartin GolkowskiIrvin GarciaRenay BauerHo-Tak LauKevin M SullivanLorene K LangebergShao-En OngKimberly J RiehleRaymond S YeungJohn D ScottPublished in: eLife (2019)
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.
Keyphrases
- heat shock protein
- protein kinase
- signaling pathway
- pi k akt
- heat shock
- transcription factor
- induced apoptosis
- cell proliferation
- acute myeloid leukemia
- cell cycle arrest
- heat stress
- single cell
- tyrosine kinase
- stem cells
- binding protein
- gene expression
- emergency department
- cell death
- dna binding
- mesenchymal stem cells
- endoplasmic reticulum stress
- acute lymphoblastic leukemia