RBBP9: A tumor-associated serine hydrolase activity required for pancreatic neoplasia

Department of Pathology, Moores Cancer Center, University of California, San Diego, CA 92093-0803, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2010; 107(5):2189-94. DOI: 10.1073/pnas.0911646107
Source: PubMed


Pancreatic cancer is one of the most lethal malignancies. To discover functionally relevant modulators of pancreatic neoplasia, we performed activity-based proteomic profiling on primary human ductal adenocarcinomas. Here, we identify retinoblastoma-binding protein 9 (RBBP9) as a tumor-associated serine hydrolase that displays elevated activity in pancreatic carcinomas. Whereas RBBP9 is expressed in normal and malignant tissues at similar levels, its elevated activity in tumor cells promotes anchorage-independent growth in vitro as well as pancreatic carcinogenesis in vivo. At the molecular level, RBBP9 activity overcomes TGF-beta-mediated antiproliferative signaling by reducing Smad2/3 phosphorylation, a previously unknown role for a serine hydrolase in cancer biology. Conversely, loss of endogenous RBBP9 or expression of mutationally inactive RBBP9 leads to elevated Smad2/3 phosphorylation, implicating this serine hydrolase as an essential suppressor of TGF-beta signaling. Finally, RBBP9-mediated suppression of TGF-beta signaling is required for E-cadherin expression as loss of the serine hydrolase activity leads to a reduction in E-cadherin levels and a concomitant decrease in the integrity of tumor cell-cell junctions. These data not only define a previously uncharacterized serine hydrolase activity associated with epithelial neoplasia, but also demonstrate the potential benefit of functional proteomics in the identification of new therapeutic targets.

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    • "The study of Shields et al. [44] on retinoblastoma-binding protein (RBBP) 9, a tumor-associated serine hydrolase, is worth noting. By using LC/LC MS/MS, activity-based proteomic profiling (ABPP) coupled to MudPIT, immunoprecipitation, and immunoblot, these authors found that RBBP9 displayed elevated activity in pancreatic carcinomas, which overcame TGF-beta-mediated antiproliferative signaling by reducing Smad2/3 phosphorylation. "
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    ABSTRACT: Pancreatic cancer is a highly aggressive malignancy with a poor prognosis and deeply affects the life of people. Therefore, the earlier diagnosis and better treatments are urgently needed. In recent years, the proteomic technologies are well established and growing rapidly and have been widely applied in clinical applications, especially in pancreatic cancer research. In this paper, we attempt to discuss the development of current proteomic technologies and the application of proteomics to the field of pancreatic cancer research. This will explore the potential perspective in revealing pathogenesis, making the diagnosis earlier and treatment.
    Full-text · Article · Aug 2011
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    ABSTRACT: We consider soft decoding of multilevel codes consisting of a partitioned inner convolutional code and several outer Reed-Solomon (RS) codes. The decoding is done in a multistage manner using a posteriori probability (APP) decoding for the convolutional code and an algebraic soft-input decoder proposed by R. Kotter and A. Vardy (see Proc. of IEEE Int. Symposium on Information Theory, p.61, 2000) for the RS codes. We present a lower bound on the minimum distance and some simulation results
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    Full-text · Article · Feb 2010 · Proceedings of the National Academy of Sciences
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