文章基本信息

标题：Structural insights into mis-regulation of protein kinase A in human tumors
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作者：Jonah Cheung ; Christopher Ginter ; Michael Cassidy 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1374-1379
DOI：10.1073/pnas.1424206112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMutations in the catalytic subunit of protein kinase A (PKA) have been found in tumors associated with the kidney disorder Cushing's syndrome and with the rare liver cancer fibrolamellar hepatocellular carcinoma (FL-HCC). Crystal structures and biochemical characterizations of the relevant PKA mutants clarify the molecular basis for disease caused by these mutations. We find contrasting underlying mechanisms for increased PKA signaling in these cancers. In Cushing's syndrome, the L205R PKA mutation abolishes regulatory-subunit binding, whereas in FL-HCC, the recurring DnaJ-PKA fusion that results from a chromosomal deletion exhibits wild-type characteristics, but is overproduced by a more active promoter. Our findings provide a structural basis for designing selective drugs that may lead to effective treatments for these diseases. The extensively studied cAMP-dependent protein kinase A (PKA) is involved in the regulation of critical cell processes, including metabolism, gene expression, and cell proliferation; consequentially, mis-regulation of PKA signaling is implicated in tumorigenesis. Recent genomic studies have identified recurrent mutations in the catalytic subunit of PKA in tumors associated with Cushing's syndrome, a kidney disorder leading to excessive cortisol production, and also in tumors associated with fibrolamellar hepatocellular carcinoma (FL-HCC), a rare liver cancer. Expression of a L205R point mutant and a DnaJ-PKA fusion protein were found to be linked to Cushing's syndrome and FL-HCC, respectively. Here we reveal contrasting mechanisms for increased PKA signaling at the molecular level through structural determination and biochemical characterization of the aberrant enzymes. In the Cushing's syndrome disorder, we find that the L205R mutation abolishes regulatory-subunit binding, leading to constitutive, cAMP-independent signaling. In FL-HCC, the DnaJ-PKA chimera remains under regulatory subunit control; however, its overexpression from the DnaJ promoter leads to enhanced cAMP-dependent signaling. Our findings provide a structural understanding of the two distinct disease mechanisms and they offer a basis for designing effective drugs for their treatment.
关键词：cancer mutations ; Cushing’s syndrome ; fibrolamelllar hepatocellular carcinoma ; chimeric protein