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 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.
Highlights
Fibrolamellar carcinoma (FLC) is a variant of liver cancer that has distinctive histologic features (Craig et al, 1980)
This unique Protein Kinase (PKA) fusion is solely expressed in FLCs, remains responsive to the second messenger cAMP, and importantly is incorporated by A-Kinase Anchoring proteins (AKAPs) into signaling complexes (Riggle et al, 2016a; Riggle et al, 2016b; Turnham and Scott, 2016)
We found that AKAP-Lbc protein is up-regulated in human FLCs as compared to normal adjacent liver (Figure 5B, top panel, lane 2) and immunoblot analysis detected DNAJ-PKAc in AKAP-Lbc immune complexes isolated from FLCs (Figure 5C, top panel, lane 2)
Summary
Fibrolamellar carcinoma (FLC) is a variant of liver cancer that has distinctive histologic features (Craig et al, 1980). Smith et al have used gene editing to make mouse liver cells that mimic the human FLC mutation Biochemical experiments on these cells showed that the DNAJ-PKAc protein brings together unique combinations of enzymes that drive uncontrolled cell growth. Whole exome sequencing from independent patient cohorts have identified pathological mutations in PKAc that are linked to Cushing’s syndrome (Sato et al, 2014) This disease occurs either as consequence of pituitary tumors that overproduce adrenocorticotropic hormone (ACTH) or as a consequence of aberrant signaling events that stimulate excess cortisol release from the adrenal glands (Beuschlein et al, 2014; Lacroix et al, 2015). The association of Hsp with DNAJ-PKAc creates a unique therapeutic target for combinations of Hsp and kinase inhibitor drugs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
