Department of Pharmacology, University of Washington Medical Center, Seattle, United States.
Department of Surgery, University of Washington Medical Center, Seattle, United States.
Elife. 2019 May 7;8:e44187. doi: 10.7554/eLife.44187.
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 AML12 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 AML12 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.
纤维板层样肝细胞癌（fibrolamellar carcinoma，FLC）是一种罕见的肝癌。FLC 独特地产生 DNAJ-PKAc，这是一种嵌合酶，由伴侣蛋白结合域与蛋白激酶 A 的 Cα亚基融合而成。对临床样本的生化分析表明，这种融合酶的一个独特特性是能够募集热休克蛋白 70（Hsp70）。这种细胞伴侣蛋白在癌症中经常上调。对小鼠肝细胞的基因编辑生成了与疾病相关的 AML12 细胞系。进一步的分析表明，原癌基因 A-激酶锚定蛋白-Lbc 在 FLC 中上调，并发挥作用将 DNAJ-PKAc/Hsp70 亚复合物与 RAF-MEK-ERK 激酶模块聚类。药物筛选显示 Hsp70 和 MEK 抑制剂组合可选择性地阻断 AML12 细胞的增殖。磷酸化蛋白质组学分析表明，DNAJ-PKAc 使信号通路偏向于 ERK 激活，并参与下游激酶级联反应。因此，DNAJ-PKAc 的致癌作用涉及获得性支架功能，允许募集 Hsp70 和动员局部 ERK 信号。
