Local Kinase Signaling in Fibrolamellar Carcinoma

Fibrolamellar carcinoma (FLC) is a rare adolescent liver cancer with unique molecular features. FLC emanates from a genetic lesion on chromosome 19 that generates a de novo fusion gene product consisting of the chaperonin-binding domain of Hsp40 (DNAJ), and the catalytic subunit of PKA. Recent work in the Scott lab has found that this chimeric enzyme, DNAJ-PKAc, can recruit heat shock protein 70, a chaperonin protein often upregulated in cancers. The focus of my work is determining the molecular interactions and signaling events responsible for driving this intractable liver cancer. Through a combination of chemical biology, cellular biochemistry, and proteomic approaches in disease-relevant cell lines, I am defining the molecular mechanism of DNAJ-PKAc action and the unique repertoire of substrates that this cancer causing fusion kinase phosphorylates.

Relevant papers for FLC:

Turnham RE, Smith FD, Kenerson HL, Omar MH, Golkowski M, Garcia I, Bauer R, Lau HT, Sullivan KM, Langeberg LK,

Ong SE, Riehle KJ, Yeung RS, Scott JD. An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma. Elife. 2019 May 7;8:e44187. doi: 10.7554/eLife.44187.

Dinh TA, Sritharan R, Smith FD, Francisco AB, Ma RK, Bunaciu RP, Kanke M, Danko CG, Massa AP, Scott JD, Sethupathy P. Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal candidate oncogenic pathways and therapeutic vulnerabilities. Cell Rep. 2020 Apr 14;31(2):107509. doi: 10.1016/j.celrep.2020.03.073.