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Activity-based protein profiling for biochemical pathway discovery in cancer

Nature Reviews Cancer volume 10, pages 630–638 (2010)Cite this article

Subjects

Key Points

  • Activity-based protein profiling (ABPP) facilitates the discovery of deregulated enzymes in cancer.

  • Competitive ABPP yields selective inhibitors for functional characterization of cancer enzymes.

  • ABPP can be integrated with metabolomics to map deregulated enzymatic pathways in cancer.

  • ABPP can be integrated with other proteomic methods to map proteolytic pathways in cancer.

  • ABPP probes can be used to image tumour development in living animals.

Abstract

Large-scale profiling methods have uncovered numerous gene and protein expression changes that correlate with tumorigenesis. However, determining the relevance of these expression changes and which biochemical pathways they affect has been hindered by our incomplete understanding of the proteome and its myriad functions and modes of regulation. Activity-based profiling platforms enable both the discovery of cancer-relevant enzymes and selective pharmacological probes to perturb and characterize these proteins in tumour cells. When integrated with other large-scale profiling methods, activity-based proteomics can provide insight into the metabolic and signalling pathways that support cancer pathogenesis and illuminate new strategies for disease diagnosis and treatment.

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Figure 1: Activity-based protein profiling.
Figure 2: Serine hydrolases KIAA1363 and MAGL regulate lipid metabolic pathways that support cancer pathogenesis.
Figure 3: Proteomic strategies for mapping protease substrates.

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Acknowledgements

This work was supported by the US National Institutes of Health (CA087660 and CA132630), the American Cancer Society (D.K.N.), the California Breast Cancer Research Foundation (M.M.D.), the ARCS Foundation (M.M.D.) and the Skaggs Institute for Chemical Biology.

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  1. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Daniel K. Nomura, Melissa M. Dix & Benjamin F. Cravatt

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Glossary

Bio-orthogonal chemical handle

A chemical handle that can be specifically modified with reporter tags within the confines of a biological environment.

Click chemistry

Chemistry that allows for quick and reliable joining of small units; the most commonly used click-chemistry reaction is the Huisgen azide-alkyne cycloaddition using a copper catalyst.

Intravasating

A process in cancer metastasis in which the cancer cells invade through the basement membrane into blood vessels.

Ether lipid

A lipid in which one or more of the oxygens on a glycerol backbone is bonded to an alkyl chain by an ether linkage.

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Nomura, D., Dix, M. & Cravatt, B. Activity-based protein profiling for biochemical pathway discovery in cancer. Nat Rev Cancer 10, 630–638 (2010). https://doi.org/10.1038/nrc2901

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