title: Enzyme activity profiles of the secreted and membrane proteome that depict cancer cell invasiveness.
abstract: By primarily measuring changes in transcript and protein abundance, conventional genomics and proteomics methods may fail to detect significant posttranslational events that regulate protein activity and, ultimately, cell behavior. To address these limitations, activity-based proteomic technologies that measure dynamics in protein function on a global scale would be of particular value. Here, we describe the application of a chemical proteomics strategy to quantitatively compare enzyme activities across a panel of human breast and melanoma cancer cell lines. A global analysis of the activity, subcellular distribution, and glycosylation state for the serine hydrolase superfamily resulted in the identification of a cluster of proteases, lipases, and esterases that distinguished cancer lines based on tissue of origin. Strikingly, nearly all of these enzyme activities were down-regulated in the most invasive cancer lines examined, which instead up-regulated a distinct set of secreted and membrane-associated enzyme activities. These invasiveness-associated enzymes included urokinase, a secreted serine protease with a recognized role in tumor progression, and a membrane-associated hydrolase KIAA1363, for which no previous link to cancer had been made. Collectively, these results suggest that invasive cancer cells share discrete proteomic signatures that are more reflective of their biological phenotype than cellular heritage, highlighting that a common set of enzymes may support the progression of tumors from a variety of origins and thus represent attractive targets for the diagnosis and treatment of cancer.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Nadim
authors.initials: N
authors.lastname: Jessani
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Liu
authors.forename: Mark
authors.initials: M
authors.lastname: Humphrey
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000145:classification / Q000201:enzymology* / Q000503:physiopathology; D002462:Cell Membrane / Q000201:enzymology; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D008545:Melanoma / Q000145:classification / Q000201:enzymology* / Q000503:physiopathology; D009361:Neoplasm Invasiveness; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D012995:Solubility; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D020543:Proteome; D006867:Hydrolases; D012697:Serine Endopeptidases