| Summary: | 博士 === 國立陽明大學 === 生物醫學資訊研究所 === 105 === English Abstract
As a growing number of cancer or disease marker candidates are identified, the field of biomarker discovery has become emerging in biological research and medical diagnostic practice. Because of the emergence of clinically non-invasive and easily accessible biomarkers, the identification of secreted protein markers has been receiving great attention as the trend toward non-invasive biomarker discovery. Allthough most secreted proteins undergo protein secretion through the secretory pathway, certain cell membrane proteins are also known to be released into the
extracellular milieu via ectodomain shedding. The proteolytic cleavage of cell membrane molecules has been shown regulate various physiological and diseases processes. Therefore, the cleaved and released membrane proteins resulting from shedding events may comprise additional resources of non-invasive and accessible biomarkers. Previous studies on membrane proteins revealed that only about 2% or 4% of cell surface molecules undergo the shedding process; hence, it is apparent that not every membrane protein will be released through proteolytic shedding. In this context, to assess whether a membrane-bound protein will be released from cells and identify membrane-bound shed markers that are of clinical potential has become indispensable.
In this thesis, a computational model-based classifier ShedP was first developed to predict the ectodomain shedding events of membrane proteins. By integrating ShedP with other state-of-the-art predictors, a screening pipeline, SecretePipe, has been created that is able to identify secreted nonmembrane proteins on the basis of signal peptides and to identify released membrane proteins on the basis of ectodomain
shedding. Our predictive results revealed that SecretePipe outperformed other state-of-the-art secreted protein predictors when against secretome data sets. SecretePipe performed better than other predictors in identifying membrane-bound released proteins due to the presence of ShedP. The augmented ability to identify shedding events of membrane proteins gives the pipeline SecretePipe great potential in terms of non-invasive biomarker discovery.
In addition, an ectodomain shedding database SheddomeDB was also developed in the study. By collecting the membrane proteins that were verified to be cleaved or released from public available data, SheddomeDB was dedicated to serve as a data repository for biological and clinical researchers to reviewing the experimentally validated shedding information of membrane-bound shed proteins. From 445 study literatures on shedding, 401 validated shed membrane proteins were included, among which 199 shed membrane proteins have not been annotated or validated yet by existing cleavage databases. SheddomeDB attempted to provide a comprehensive shedding report, including the regulation of shedding machinery and the related function or diseases involved in the shedding events. SheddomeDB may be a useful bioinformatics design for non-invasive marker discovery and to help investigate the regulatory role of membrane proteins in physiological and pathological processes.
Thus, as more membrane-bound proteins are identified as released via shedding and more and more studies have revealed the regulatory role of ectodomain shedding in various cellular processes and pathologies, the identification of shed and released membrane proteins is becoming important in the field of non-invasive marker discovery and sheddome proteomics. To facilitate the researches in membrane protein shedding and provide a valuable resource for cell biologists and clinical researchers,we provided two bioinformatics designs in the current study. First, the proposed SecretePipe that incorporated the shedding event predictor ShedP helps to assess the likelihood of an unknown or unrecorded membrane protein to be cleaved and released from the cell. Next, the database SheddomeDB summarized exsiting shedding information, which is experimentally validated, for membrane-bound shed protein. The two designs are publicly available at http://bal.ym.edu.tw/SecretePipe/ and http://bal.ym.edu.tw/SheddomeDB/, respectively.
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