Substrate Profiling of Cysteine Proteases in Physiology and Pathology
Zusammenfassung der Projektergebnisse
Proteolytic processing affects every protein, leading to stable cleavage products with altered functionality or protein degradation. “Degradomics” describes novel functional proteomic tools, which investigate proteolytic processing in the cellular context. The Emmy-Noether project successfully established a “degradomics” laboratory that is well integrated in the local, national, and international scientific community. The Emmy-Noether project further enhanced the degradomic toolbox, e.g. through proteome-wide analysis of protein C-termini. Furthermore, clinical degradomics has been enabled by developing N-terminomic techniques for the analysis of archived, formalin-fixed, paraffinembedded specimens. Also, the usage of proteome-derived peptide libraries for the in vitro determination of protease specificity has been enhanced by a refined, more robust workflow. The project has largely focused on cysteine cathepsins due to their prominent implications in numerous (patho-)physiological processes. Proteomic and degradomic studies on cysteine cathepsins have been conducted on the in vitro, cell-contextual, and in vivo level. A novel link between cysteine cathepsins, matrix metalloproteases, and the matricellular protein periostin has been uncovered. At the same time, novel, non-enzymatic cathepsin functions are being equally investigated.
Projektbezogene Publikationen (Auswahl)
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Isotopic labeling of terminal amines in complex samples identifies protein N-termini and protease cleavage products. Nat Biotechnol. 2010 Mar;28(3):281-8
Kleifeld O, Doucet A, auf dem Keller U, Prudova A, Schilling O, Kainthan RK, Starr AE, Foster LJ, Kizhakkedathu JN, Overall CM
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Proteome-wide analysis of protein carboxy termini: C terminomics. Nat Methods. 2010 Jul;7(7):508-11
Schilling O, Barré O, Huesgen PF, Overall CM
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Proteomic identification of protease cleavage sites characterizes prime and non-prime specificity of cysteine cathepsins B, L, and S. J Proteome Res. 2011 Dec 2;10(12):5363-73
Biniossek ML, Nägler DK, Becker-Pauly C, Schilling O
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Deletion of cysteine cathepsins B or L yields differential impacts on murine skin proteome and degradome. Mol Cell Proteomics. 2013 Mar;12(3):611-25
Tholen S, Biniossek ML, Gansz M, Gomez-Auli A, Bengsch F, Noel A, Kizhakkedathu JN, Boerries M, Busch H, Reinheckel T, Schilling O
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Double deficiency of cathepsins B and L results in massive secretome alterations and suggests a degradative cathepsin-MMP axis. Cell Mol Life Sci. 2014 Mar;71(5):899-916.
Tholen S, Biniossek ML, Gansz M, Ahrens TD, Schlimpert M, Kizhakkedathu JN, Reinheckel T, Schilling O
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Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells. Mol Oncol. 2014 Feb;8(1):68-82
Shahinian H, Loessner D, Biniossek ML, Kizhakkedathu JN, Clements JA, Magdolen V, Schilling O
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Enrichment of protein N-termini by charge reversal of internal peptides. Proteomics. 2015 Jul;15(14):2470-8
Lai ZW, Gomez-Auli A, Keller EJ, Mayer B, Biniossek ML, Schilling O
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Lysosomal protein turnover contributes to the acquisition of TGFβ-1 induced invasive properties of mammary cancer cells. Mol Cancer. 2015 Feb 15;14:39
Kern U, Wischnewski V, Biniossek ML, Schilling O, Reinheckel T
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miR-200c dampens cancer cell migration via regulation of protein kinase A subunits. Oncotarget. 2015 Sep 15; 6(27): 23874–23889
Sigloch FC, Burk UC, Biniossek ML, Brabletz T, Schilling O
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The stromal cell-surface protease fibroblast activation protein-α localizes to lipid rafts and is recruited to invadopodia. Biochim Biophys Acta. 2015 Jul 22. pii: S0167-4889
Knopf JD, Tholen S, Koczorowska MM, De Wever O, Biniossek ML, Schilling O
