George ButlerGeorge-Butler_Chris-Overall-Lab_500x500

Since July 2024 –  Senior Grant Writer in the Hill Lab, Department of Chemical and Biological Engineering, UBC

Hill Lab



Research Associate in the Overall lab from 01/1999 – 06/2024

Centre for Blood Research
University of British Columbia
2350 Health Sciences Mall
Vancouver, BC, V6T 1Z3, Canada

Office: #4.402, Lab: #4.420, Bench 2. 
Phone: +1-604-822-8233 (office), +1-604-822-3561 (lab)
Email: george.butler (a)


  • BSc (Hons.) Biochemistry with studies in Italy. University of Kent at Canterbury, UK (1991)  (Including 1 year at University of Bologna, Italy  as part of the ERASMUS student exchange program )
  • PhD Biochemistry University of Leicester, UK (1997)


  • 1995 – 1997: Postdoctoral Scientist with Prof. G. Murphy, Strangeways Research Laboratory, Cambridge, U.K.
  • 1997 –1998:  Senior Research Associate with Prof. G. Murphy, University of East Anglia, Norwich, U.K.
  • 1999 –2000: Wellcome Trust U.K. Travelling Fellow with Prof. C. Overall, University of British Columbia, Vancouver, Canada.
  • 2001 – 2002: Postdoctoral Scientist with Prof. C. Overall, University of British Columbia, Vancouver, Canada.
  • 2003 – present: Research Associate with Prof. C. Overall, University of British Columbia, Vancouver, Canada.

Research Interests

My work in Gill Murphy’s lab in Cambridge focused on the interactions of tissue inhibitors of metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs). I participated in the characterisation of the newly discovered membrane-type matrix metalloproteinases MT1-MMP and MT2-MMP, characterisation of TIMP3, and the elucidation of the mechanism of activation of proMMP2 (gelatinase A) by MT1-MMP and TIMP2. When I moved to Chris Overall’s lab in Vancouver, I continued to be interested in structure-function relationships of MMPs and TIMPs. At that time, we still thought of the MMP family solely in terms of extracellular matrix (ECM) degradation. Undoubtedly these proteases are important for ECM remodelling for example, playing a critical role at several stages of metastasis, but the disappointing outcome of cancer clinical trials of MMP inhibitors indicated that these proteases might do more than remodel matrix. Since the function of a protease is dictated by the functions of the substrates that are cleaved and the changes that this proteolytic processing imparts on the substrate, in the Overall Lab we have been applying proteomics to look for new substrates of MMPs. This application of proteomics, i.e. degradomics, has really revolutionised the way that we think about MMPs – due to the unbiased nature of proteomics, these screens are revealing aspects of MMP biology that we would probably never think to investigate based on existing knowledge. By taking cell systems or tissues with differing amounts of MMP activity (e.g. wild-type vs knockout mouse or  cells expressing protease versus vector control) and comparing them using quantitative proteomics and more recently N-terminomics, we have been able to identify substrates and cleavage sites in a variety of proteins. Currently I am investigating how MMP cleavage alters the biological functions of some of these novel substrates.

Selected Publications

  • Fortelny, N., Butler, G.S., Overall, C.M., Pavlidis, P. Analysis of Protein-Protein Interaction and Gene Exression in the Prediction of Protease Inhibitors and Target Proteases in the Protease Web. Science Signalling. 2015; submitted
  • Eckhard, U., Marino, G., Butler, G.S., Overall, C.M. Positional Proteomics in the Era of the Human Proteome Project, Identifying Proteolytic Signatures as Biomarkers of Disease for Diagnosis to Monitor Progression, and to Personalised Medicine. Biochimie. 2016. 122: 110-118.
  • Eckhard, U., Huesgen, P.F., Schilling, O., Bellac, C.L., Butler, G.S., Cox, J.H., Dufour, A., Goebeler, V., Kappelhoff, R., auf dem Keller, U., Klein, T., Lange, P.F., Marino, G., Morrison, C.J., Prudova, A., Rodriguez, D., Starr, A.E., Wang, Y., Overall, C.M. Active site specificity of the matrix metalloproteinase family: Proteomic identification of 4300 cleavage sites by nine MMPs explored with structural and synthetic peptide cleavage assays. Matrix Biology. In press. doi:10.1016/j.matbio.2015.09.003
  • Bellac, C.L., Dufour, A., Krisinger, M.J., Loonchanta, A., Starr, A.E., auf dem Keller, U., Lange, P.F., Goebeler, V., Kappelhoff, R., Butler, G.S., Burtnik, L.D., Conway, E.M., Roberts, C.R., Overall, C.M. Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis. Cell Reports. 2014. 9:1-15.
  • Marchant, D. J., Bellac, C. L., Moraes, T. J., Wadsworth, S. J., Dufour, A., Butler, G. S., Bilawchuk, L. M., Hendry, R. G., Robertson, A. G., Cheung, C. T., Ng, J., Ang, L., Luo, Z., Heilbron, K., Norris, M. J., Duan, W., Bucyk, T., Karpov, A., Devel, L., Georgiadis, D., Hegele, R. G., Luo, H., Granville, D. J., Dive, V., McManus, B. M., and Overall, C. M. A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity. Nat Med. 2014;20(5): 493-502
  • Butler, G. S., and Overall, C. M. Matrix metalloproteinase processing of signaling molecules to regulate inflammation. Periodontol 2000. 2013;63(1):123-148.
  • Patel, T. R., Butler, G., McFarlane, A., Xie, I., Overall, C. M., Stetefeld, J. Site specific cleavage mediated by MMPs regulates function of agrin. PLoS One. 2012; 7(9):e43669.
  • Butler GS, Dean RA, Morrison CJ, Overall CM. Identification of cellular MMP substrates using quantitative proteomics: isotope-coded affinity tags (ICAT) and isobaric tags for relative and absolute quantification (iTRAQ). Methods Mol Biol. 2010;622:451-70.
  • Prudova A, auf dem Keller U, Butler GS, Overall CM. Multiplex N-terminome analysis of MMP-2 and MMP-9 substrate degradomes by iTRAQ-TAILS quantitative proteomics. Mol Cell Proteomics. 2010 May;9(5):894-911.
  • auf dem Keller U, Prudova A, Gioia M, Butler GS, Overall CM. A statistics-based platform for quantitative N-terminome analysis and identification of protease cleavage products. Mol Cell Proteomics. 2010 May;9(5):912-27.
  • Butler GS, Overall CM. Proteomic identification of multitasking proteins in unexpected locations complicates drug targeting. Nat Rev Drug Discov. 2009 Dec;8(12):935-48.
  • Butler GS, Overall CM. Updated biological roles for matrix metalloproteinases and new “intracellular” substrates revealed by degradomics. Biochemistry. 2009 Nov 24;48(46):10830-45.
  • Butler, G. S., Dean, R. A., Smith, D., and Overall, C. M. (2009) Membrane protease degradomics: proteomic identification and quantification of cell surface protease substrates, Methods Mol Biol 528, 159-176.
  • Morrison CJ, Butler GS, Rodriguez D, Overall CM. Matrix metalloproteinase proteomics: substrates, targets, and therapy. Curr Opin Cell Biol. 2009 Oct;21(5):645-53.
  • Doucet, A., Butler, G. S., Rodriguez, D., Prudova, A., and Overall, C. M. (2008) Metadegradomics: toward in vivo quantitative degradomics of proteolytic post-translational modifications of the cancer proteome, Mol Cell Proteomics 7, 1925-1951.
  • Butler, G.S., R.A. Dean, E. Tam, and C.M. Overall. 2008. Pharmacoproteomics of a metalloproteinase hydroxamate inhibitor in breast cancer cells: Dynamics of matrix metalloproteinase-14 (MT1-MMP) mediated membrane protein shedding. Mol Cell Biol. 28:4896-4914.
  • Overall, C.M. and G.S. Butler. 2007. Protease yoga: extreme flexibility of a matrix metalloproteinase. Structure. 15:1159-61.
  • Dean, R.A., Butler, G.S., Hamma-Kourbali, Y., Delbé, J., Courty, J. and Overall, C.M. 2007. A New Role of MMP-2 in Angiogenesis Revealed by Proteomic Analysis: Identification of HARP (Pleiotrophin) and CTGF as Novel Substrates of MMP-2. Mol. Cell. Biol. 2007 27 (24) 8454-65.
  • Butler, G.S. and C.M. Overall. 2007. Proteomic validation of protease drug targets: pharmacoproteomics of matrix metalloproteinase inhibitor drugs using isotope-coded affinity tag labelling and tandem mass spectrometry. Curr Pharm Des. 13:263-70.
  • Vergote, D, Butler, GS, Ooms, M, Cox, JH, Silva, C, Hollenberg, MD, Jhamandas, JH, Overall, CM, Power, C. Proteolytic processing of SDF-1alpha reveals a change in receptor specificity mediating HIV-associated neurodegeneration. Proc Natl Acad Sci USA 2006 103 (50) 19182-7
  • Nisato, RE, Hosseini, G, Sirrenberg, C, Butler, GS, Crabbe, T, Docherty, A. J, Wiesner, M, Murphy, G, Overall, CM, Goodman, SL, Pepper, MS. Dissecting the role of matrix metalloproteinases (MMP) and integrin alpha(v)beta3 in angiogenesis in vitro: absence of hemopexin C domain bioactivity, but membrane-Type 1-MMP and alpha(v)beta3 are critical. Cancer Res 2005 65 (20) 9377-87
  • Butler, GS, Tam, EM, Overall, C. M. The canonical methionine 392 of matrix metalloproteinase 2 (gelatinase A) is not required for catalytic efficiency or structural integrity: probing the role of the methionine-turn in the metzincin metalloprotease superfamily. J Biol Chem 2004 279 (15) 15615-20
  • Tam, EM, Moore, TR, Butler, GS, Overall, C.M. Characterization of the distinct collagen binding, helicase and cleavage mechanisms of matrix metalloproteinase 2 and 14 (gelatinase A and MT1-MMP): the differential roles of the MMP hemopexin c domains and the MMP-2 fibronectin type II modules in collagen triple helicase activities. J Biol Chem 2004 279 (41) 43336-44
  • Zhang K, McQuibban GA, Silva C, Butler GS, Johnston JB, Holden J, Clark-Lewis I, Overall CM, Power C. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci. 2003 6 1064-71.
  • Kai HS, Butler GS, Morrison CJ, King AE, Pelman GR, Overall CM. Utilization of a novel recombinant myoglobin fusion protein expression system to characterize the tissue inhibitor of metalloproteinase (TIMP)-4 and TIMP-2 C-terminal domain and tails by mutagenesis. The importance of acidic residues in binding the MMP-2 hemopexin C-domain. J Biol Chem. 2002 277 48696-707.
  • Tam EM, Wu YI, Butler GS, Stack MS, Overall CM. Collagen binding properties of the membrane type-1 matrix metalloproteinase (MT1-MMP) hemopexin C domain. The ectodomain of the 44-kDa autocatalytic product of MT1-MMP inhibits cell invasion by disrupting native type I collagen cleavage. J Biol Chem. 2002 277 39005-14.
  • GS Butler, D Sim, E Tam, D Devine, CM Overall Mannose Binding Lectin (MBL) Mutants are Susceptible to Metalloproteinase Proteolysis: Potential Role in MBL Deficiency. J Biol Chem. 2002 277 17511-9.
  • CJ Morrison, GS Butler, HF Bigg, CR Roberts, PD Soloway, and CM Overall Cellular activation of MMP-2 (Gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway. J Biol Chem. 2001 276 47402-47410.
  • McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I, and Overall CM. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem. 2001 276 43503-43508.
  • Bigg HF, Morrison CJ, Butler GS, Bogoyevitch MA, Wang Z, Soloway PD & Overall CMTissue Inhibitor of Metalloproteinase-4 Inhibits But Does Not Support the Activation of Gelatinase A Via Efficient Inhibition of Membrane Type 1-Matrix Metalloproteinase. Cancer Res. 2001 61 3610-3618.
  • Butler GS, Hutton M, Wattam BA, Williamson RA, Knauper V, Willenbrock F & Murphy G The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations. J Biol Chem. 1999 274 20391-20396.
  • Butler GS, Apte S, Willenbrock F & Murphy G Human Tissue Inhibitor of Metalloproteinases 3 interacts with both the N- and C-terminal domains of gelatinases A and B. Regulation by polyanions. J Biol Chem. 1999 274 10846-10851.
  • Hutton M, Butler GS, Wattam BA, Willenbrock F, Williamson RA & Murphy G. Analysis of the interaction of TIMP-2 and MMPs: engineering the changes. Ann NY Acad Sci. 1999 878 524-527.
  • Murphy G, Knauper V, Cowell S, Hembry R, Stanton H, Butler G, Freije J, Pendas A & Lopez-Otin C. Evaluation of some newer metalloproteinases. Ann N.Y. Acad. Sci. 1999 878 25-39
  • Murphy G, Stanton H, Cowell S, Butler G, Knauper V, Atkinson S & Gavrilovic J. Mechanisms for pro matrix metalloproteinase activation. APMIS 1999 107 38-44.
  • Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, Schade van Westrum S, Crabbe T, Clements J, d’Ortho MP & Murphy G. The TIMP2-membrane-type 1 metalloproteinase ‘receptor’ regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem. 1998 273 871-880.
  • d’Ortho MP, Will H, Atkinson S, Butler G, Messent A, Gavrilovic J, Smith B, Timpl R, Zardi L & Murphy G. Membrane-type matrix metalloproteinases 1 and 2 exhibit a broad spectrum proteolytic capacity comparable to many matrix metalloproteinases. Eur J Biochem. 1997 250 751-757.
  • Butler GS, Will H, Atkinson SJ & Murphy G. Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases. Eur J Biochem. 1997 244 653-657.
  • Will H, Atkinson SJ, Butler GS, Smith B & Murphy G. The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. J Biol Chem. 1996 271 17119-17123.
  • Dempsey CE & Butler GS. Helical structure and orientation of melittin dispersed in phospholipid membranes from amide exchange analysis in situ. Biochemistry 1992 31 11973-11977.
  • Degli Esposti M, Ghelli A, Butler G, Roberti M, Mustich A & Cantatore P. The cytochrome b of the sea urchin Paracentrotus lividus is naturally resistant to myxothiazol and mucidin. FEBS 1990 263 245-247.