Centre for Blood Research
University of British Columbia
2350 Health Sciences Mall
Vancouver, BC, V6T 1Z3, Canada
Lab: #4.420; Bench 4
Phone: +1-604-822-3561 (lab)
- 2008; PhD, University of Groningen (Analytical Biochemistry)
- 2004; PharmD, University of Groningen
- 2001; MSc, University of Groningen (Pharmacy, major in Analytical Chemistry)
My work focusses on elucidating the role of the protease MALT-1 in lymphocyte function. MALT-1 is a central player in activation of lymphocytes via T cell receptor or B cell receptor stimulation by acting as a scaffolding protein in the BCL-10/MALT-1/CARD11 complex, which is required for signalling by ubiquitination and phosphorylation downstream in the NFkappaB pathway. Recently discovered targets of proteolysis by MALT-1, such as the regulating deubiquitinases CYLD and A20, and the NF kappaB factor RelB show that this paracaspase has an important, yet complex role in the this pivotal pathway in lymphocytes.
In collaboration with Dr. Stuart Turvey’s lab at CFRI in Vancouver we investigate potential new roles of MALT-1 by performing proteomics and n-terminomic TAILS analysis on lymphocytes of a patient with a rare mutation in the MALT-1 gene leading to lower protein levels, and more importantly lower protease activity. Finding new targets of MALT-1 proteolysis will broaden our understanding of MALT-1 function and lymphocyte biology, and lead to novel targets in treatment of disease.
In another project I collaborate with the microbiology lab of Dr. Brett Finlay at UBC on finding out how Salmonella affects proteolytic pathways in mammalian cells. Salmonella enterica is capable of actively invading cells via a sophisticated system of secreted and injected effector molecules that modulate the intracellular environment to enable Salmonella survival and replication. The effect of these effectors on cellular processes such as phosphorylation is well studied, and in this project we hope to shed light on the effect on proteolysis. At least two Salmonella effectors are known proteases, and Salmonella is known to affect proteolytic activity by activating apoptosis at the end of the intracellular life cycle. We are using TAILS on infected cultured cells to discover unknown proteolytic events which will enable us to paint a picture of the proteolytic landscape after Salmonella infection, and will potentially lead to novel targets for preventing and healing Salmonellosis.
- Pera T, Zuidhof AB, Smit M, Menzen MH, Klein T, Flik G, Zaagsma J, Meurs H, Maarsingh H. Arginase inhibition prevents inflammation and remodeling in a guinea pig model of chronic obstructive pulmonary disease. J Pharmacol Exp Ther. 2014 May;349(2):229-38
- Maarsingh H, Dekkers BG, Zuidhof AB, Bos IS, Menzen MH, Klein T, Flik G, Zaagsma J, Meurs H. Increased arginase activity contributes to airway remodelling in chronic allergic asthma. Eur Respir J. 2011 Aug;38(2):318-28
- Klein T, Bischoff R. Active metalloproteases of the A Disintegrin and Metalloprotease (ADAM) family: biological function and structure. J Proteome Res. 2011 Jan 7;10(1):17-33
- Klein T, Bischoff R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids. 2011 Jul;41(2):271-90
- Klein T, P Geurink P, S Overkleeft H, K Kauffman H, Bischoff R. Functional proteomics on zinc-dependent metalloproteinases using inhibitor probes. ChemMedChem. 2009 Feb;4(2):164-70
- Freije R, Klein T, Ooms B, Kauffman HF, Bischoff R. An integrated high-performance liquid chromatography-mass spectrometry system for the activity-dependent analysis of matrix metalloproteases. J Chromatogr A. 2008 May 2;1189(1-2):417-25
- Geurink P, Klein T, Leeuwenburgh M, van der Marel G, Kauffman H, Bischoff R, Overkleeft H. A peptide hydroxamate library for enrichment of metalloproteinases: towards an affinity-based metalloproteinase profiling protocol. Org Biomol Chem. 2008 Apr 7;6(7):1244-50
- Leeuwenburgh MA, Geurink PP, Klein T, Kauffman HF, van der Marel GA, Bischoff R, Overkleeft HS. Solid-phase synthesis of succinylhydroxamate peptides: functionalized matrix metalloproteinase inhibitors. Org Lett. 2006 Apr 13;8(8):1705-8
Freije JR, Klein T, Ooms JA, Franke JP, Bischoff R. Activity-based matrix metallo-protease enrichment using automated, inhibitor affinity extractions. J Proteome Res. 2006 May;5(5):1186-94
- Crescenzi C, Bayoudh S, Cormack PA, Klein T, Ensing K. Determination of clenbuterol in bovine liver by combining matrix solid-phase dispersion and molecular imprinted solid-phase extraction followed by liquid chromatography/electrospray ion trap multiple-stage mass spectrometry. Anal Chem. 2001 May 15;73(10):2171-7