An Acquired Scaffolding Function of the DNAJ-PKAc Fusion Contributes to Oncogenic Signaling in Fibrolamellar Cancer
Plain Language Summary:
Fibrolamellar carcinoma (FLC) is caused by a protein chimera- a fusion between parts of two proteins. One part comes from a protein called DNAJB1. This partners with other cell proteins to help misfolded proteins take on their proper native forms. The second comes from most of an enzyme, Protein Kinase A (PKA), a kinase that can add phosphate to many proteins. That addition can change the actions of its targets, and is an important way that cells respond in a coordinated way, via PKA, to certain hormones and drugs. One important partner of DNAJB1 is heat shock protein 70 (Hsp70); this is frequently up-regulated in cancers.
In the paper described here, they took a mouse cell line called AML-12 which had been previous engineered to overexpressing human Transforming growth factor alpha (TGF-α) , which activates various pathways for cell growth. These AML-12 cells were then made to express the fusion protein which causes FLC, DNAJB1-PRKACA (PRKACA is the active subunit of PKA). Although DNAJB1-PRKACA contains only a small portion of the intact DNAJB1, it was found to still interact with the normal partner of DNAJB1, HSP70. The interaction cluster, importantly, also contained other kinases, RAF-MEK-ERK kinases, that are known to activate cell growth. Two related and supportive observations were described: Drug combinations that block Hsp70 and MEK inhibit proliferation of AML12-DNAJB1-PRKACA cells. Second, the proteins in those cells bear a pattern of phosphorylation characteristic of ERK activation. Together these data imply that the DNAJB1-PRKACA fusion protein creates a novel pathologic cluster that can drive tumor cell growth. The data invite investigation of ERK inhibitors for FLC therapy. Some caution is indicated in considering these conclusions. The AML12-DNAJ-PKAc cells lack some typical characteristics of FLC tumor cells, which might limit the extent to which they provide useful therapeutic guidance.