Scientific Publications and Presentations

An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma

May 7, 2019

Turnham, Smith, Kenerson, Omar, Golkowski, Garcia, Bauer, Lau, Sullivan, ..., Yeung & Scott
Journal article in eLife

Fibrolamellar carcinoma (FLC) is driven by the fusion protein DNAJ-PKAc. That protein is made up of two different parts, one that helps with protein folding (DNAJB1) and another (protein kinase A) that’s typically involved in cell signaling. In this study, researchers have found that DNAJ-PKAc acts like a scaffold, bringing together other proteins that contribute to the development of this cancer. One important protein it interacts with is heat shock protein 70 (Hsp70). This interaction is not supposed to happen and is part of what makes FLC unique. Normally, Hsp70 helps fix misfolded proteins, but in FLC, it stabilizes DNAJ-PKAc.

The researchers also discovered that by inhibiting Hsp70 and another protein called MEK with certain drugs, they could slow down the growth of FLC cells. This suggests that DNAJ-PKAc and the proteins it interacts with are important for the cancer to progress. They also found that FLC cells have a unique way of activating a signaling pathway called ERK, and this is linked to DNAJ-PKAc. This signaling pathway may be crucial for the cancer’s growth.

The researchers believe that the unusual DNAJ-PKAc protein and its interactions with other proteins are key factors in how FLC develops. The study suggests that a combination of Hsp70 and MEK inhibition may offer a potential combination therapy for FLC. However, that utility is not clear and should be tested in other model systems in addition to the engineered AML-12 system used in this study.

The full text of the published paper can be accessed here.

Note: The research effort behind this article was partially funded by FCF.