An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma
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...
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eLife Sciences Publications Ltd
2019-05-01
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| Online Access: | https://elifesciences.org/articles/44187 |
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doaj-df0373e02b8847ebb7435e13a15b41eb2021-05-05T17:35:40ZengeLife Sciences Publications LtdeLife2050-084X2019-05-01810.7554/eLife.44187An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinomaRigney E Turnham0F Donelson Smith1https://orcid.org/0000-0002-8080-7589Heidi L Kenerson2Mitchell H Omar3Martin Golkowski4Irvin Garcia5Renay Bauer6Ho-Tak Lau7Kevin M Sullivan8Lorene K Langeberg9https://orcid.org/0000-0002-3760-7813Shao-En Ong10Kimberly J Riehle11Raymond S Yeung12John D Scott13https://orcid.org/0000-0002-0367-8146Department of Pharmacology, University of Washington Medical Center, Seattle, United StatesDepartment of Pharmacology, University of Washington Medical Center, Seattle, United StatesDepartment of Surgery, University of Washington Medical Center, Seattle, United StatesDepartment of Pharmacology, University of Washington Medical Center, Seattle, United StatesDepartment of Pharmacology, University of Washington Medical Center, Seattle, United StatesDepartment of Pharmacology, University of Washington Medical Center, Seattle, United StatesDepartment of Surgery, University of Washington Medical Center, Seattle, United StatesDepartment of Pharmacology, University of Washington Medical Center, Seattle, United StatesDepartment of Surgery, University of Washington Medical Center, Seattle, United StatesDepartment of Pharmacology, University of Washington Medical Center, Seattle, United StatesDepartment of Pharmacology, University of Washington Medical Center, Seattle, United StatesDepartment of Surgery, University of Washington Medical Center, Seattle, United StatesDepartment of Surgery, University of Washington Medical Center, Seattle, United StatesDepartment of Pharmacology, University of Washington Medical Center, Seattle, United StatesFibrolamellar 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.https://elifesciences.org/articles/44187Protein kinase Acombination therapyfibrolamellar carcinomaMAP kinaseintratumoral heterogeneitylocal signaling |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Rigney E Turnham F Donelson Smith Heidi L Kenerson Mitchell H Omar Martin Golkowski Irvin Garcia Renay Bauer Ho-Tak Lau Kevin M Sullivan Lorene K Langeberg Shao-En Ong Kimberly J Riehle Raymond S Yeung John D Scott |
| spellingShingle |
Rigney E Turnham F Donelson Smith Heidi L Kenerson Mitchell H Omar Martin Golkowski Irvin Garcia Renay Bauer Ho-Tak Lau Kevin M Sullivan Lorene K Langeberg Shao-En Ong Kimberly J Riehle Raymond S Yeung John D Scott An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma eLife Protein kinase A combination therapy fibrolamellar carcinoma MAP kinase intratumoral heterogeneity local signaling |
| author_facet |
Rigney E Turnham F Donelson Smith Heidi L Kenerson Mitchell H Omar Martin Golkowski Irvin Garcia Renay Bauer Ho-Tak Lau Kevin M Sullivan Lorene K Langeberg Shao-En Ong Kimberly J Riehle Raymond S Yeung John D Scott |
| author_sort |
Rigney E Turnham |
| title |
An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma |
| title_short |
An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma |
| title_full |
An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma |
| title_fullStr |
An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma |
| title_full_unstemmed |
An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma |
| title_sort |
acquired scaffolding function of the dnaj-pkac fusion contributes to oncogenic signaling in fibrolamellar carcinoma |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2019-05-01 |
| description |
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. |
| topic |
Protein kinase A combination therapy fibrolamellar carcinoma MAP kinase intratumoral heterogeneity local signaling |
| url |
https://elifesciences.org/articles/44187 |
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