Michael Kofler is an Adjunct Scientist in the lab of Dr. Andras Kapus at the Keenan Research Center for Biomedical Science of St. Michael’s Hospital.
Dr. Kofler received his PhD from the Freie Universität Berlin, Germany for the characterization of GYF protein adaptor domains in the lab of Dr. Christian Freund. Adaptor domains are building blocks found in many signaling proteins that mediate interactions with other proteins. These interactions lay the foundation for accurate cellular responses to extracellular signals. At the Lunenfeld-Tanenbaum Research Institute, Toronto, Dr. Kofler completed his postdoctoral fellowship with the late Dr. Tony Pawson where he studied the activation mechanism of the FES tyrosine kinase through its SH2 adaptor domain. Over-activation of tyrosine kinases is a common cause of cancer.
Dr. Kofler joined the lab of Dr. Andras Kapus to identify the mechanisms underlying the nuclear import, and consequently activation, of the transcriptional coactivators Yap and TAZ. Yap/TAZ drive the expression of genetic programs that are important for development, growth, and regeneration. Inappropriate activation of these coactivators are the cause of fibrosis and cancer. Currently, Dr. Kofler focuses on novel aspects of Yap/TAZ functions that are relevant to innate immunity and rely on transcription-independent functions of these molecules. He, as a part of this common endeavor, develops molecular probes for high throughput imaging to study these novel functions. This platform will also be utilized to identify Yap/TAZ inhibitors with the focus on improving broad antiviral responses.
1: Kofler M, Kapus A. Nucleocytoplasmic Shuttling of the Mechanosensitive Transcription Factors MRTF and YAP /TAZ. Methods Mol Biol. 2021;2299:197-216.doi: 10.1007/978-1-0716-1382-5_15. PMID: 34028745.
2: Speight P, Rozycki M, Venugopal S, Szászi K, Kofler M, Kapus A. Myocardin-related transcription factor and serum response factor regulate cilium turnoverby both transcriptional and local mechanisms. iScience. 2021 Jun 17;24(7):102739. doi: 10.1016/j.isci.2021.102739. PMID: 34278253; PMCID:
PMC8261663.
3: Bialik JF, Ding M, Speight P, Dan Q, Miranda MZ, Di Ciano-Oliveira C, Kofler MM, Rotstein OD, Pedersen SF, Szászi K, Kapus A. Profibrotic epithelialphenotype: a central role for MRTF and TAZ. Sci Rep. 2019 Mar 13;9(1):4323. doi:10.1038/s41598-019-40764-7. PMID: 30867502; PMCID: PMC6416270.
4: Kofler M, Speight P, Little D, Di Ciano-Oliveira C, Szászi K, Kapus A. Mediated nuclear import and export of TAZ and the underlying molecularrequirements. Nat Commun. 2018 Nov 23;9(1):4966. doi:
10.1038/s41467-018-07450-0. PMID: 30470756; PMCID: PMC6251892.
5: Speight P, Kofler M, Szászi K, Kapus A. Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFβ-regulated Smad3. Nat Commun. 2016 May 18;7:11642. doi:10.1038/ncomms11642. PMID: 27189435; PMCID: PMC4873981.
6: Zaretsky S, Rai V, Gish G, Forbes MW, Kofler M, Yu JC, Tan J, Hickey JL, Pawson T, Yudin AK. Twisted amide electrophiles enable cyclic peptide sequencing. Org Biomol Chem. 2015 Jul21;13(27):7384-8. doi: 10.1039/c5ob01050k.
PMID: 26077966.
7: Louria-Hayon I, Frelin C, Ruston J, Gish G, Jin J, Kofler MM, Lambert JP, Adissu HA, Milyavsky M, Herrington R, Minden MD, Dick JE, Gingras AC, Iscove NN, Pawson T. Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling. Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20599-604. doi: 10.1073/pnas.1319665110. Epub 2013 Dec 2.
PMID: 24297922; PMCID: PMC3870688.
8: Ash MR, Faelber K, Kosslick D, Albert GI, Roske Y, Kofler M, Schuemann M, Krause E, Freund C. Conserved beta-hairpin recognition by the GYF domains of Smy2 and GIGYF2 in mRNA surveillance and vesicular transport complexes. Structure. 2010 Aug 11;18(8):944-54. doi: 10.1016/j.str.2010.04.020. PMID:20696395.
9: Kofler M, Schuemann M, Merz C, Kosslick D, Schlundt A, Tannert A, Schaefer M, Lührmann R, Krause E, Freund C. Proline-rich sequence recognition: I. Marking GYF and WW domain assembly sites in early spliceosomal complexes. Mol Cell Proteomics. 2009 Nov;8(11):2461-73. doi: 10.1074/mcp.M900191-MCP200. Epub 2009 May 30. PMID: 19483244; PMCID: PMC2773714.
10: Pawson T, Kofler M. Kinome signaling through regulated protein-protein interactions in normal and cancer cells. Curr Opin Cell Biol. 2009 Apr;21(2):147-53. doi: 10.1016/j.ceb.2009.02.005. Epub 2009 Mar 18. PMID:19299117.
11: Filippakopoulos P, Kofler M, Hantschel O, Gish GD, Grebien F, Salah E, Neudecker P, Kay LE, Turk BE, Superti-Furga G, Pawson T, Knapp S. Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation. Cell. 2008 Sep 5;134(5):793-803. doi:10.1016/j.cell.2008.07.047. PMID: 18775312; PMCID: PMC2572732.
12: Heinze M, Kofler M, Freund C. Investigating the functional role of CD2BP2 in T cells. Int Immunol. 2007 Nov;19(11):1313-8. doi: 10.1093/intimm/dxm100. Epub 2007 Sep 29. PMID: 17906334.
13: Kofler MM, Freund C. The GYF domain. FEBS J. 2006 Jan;273(2):245-56. doi: 10.1111/j.1742-4658.2005.05078.x. PMID: 16403013.
14: Kofler M, Motzny K, Beyermann M, Freund C. Novel interaction partners of the CD2BP2-GYF domain. J Biol Chem. 2005 Sep 30;280(39):33397-402. doi: 10.1074/jbc.M503989200. Epub 2005 Jul 6. PMID: 16000308.
15: Piotukh K, Gu W, Kofler M, Labudde D, Helms V, Freund C. Cyclophilin A binds to linear peptide motifs containing a consensus that is present in many humanproteins. J Biol Chem. 2005 Jun 24;280(25):23668-74. doi:10.1074/jbc.M503405200. Epub 2005 Apr 21. PMID: 15845542.
16: Heuer K, Arbuzova A, Strauss H, Kofler M, Freund C. The helically extended SH3 domain of the T cell adaptor protein ADAP is a novel lipid interaction domain. J Mol Biol. 2005 May 13;348(4):1025-35. doi: 10.1016/j.jmb.2005.02.069. PMID: 15843031.
17: Gu W, Kofler M, Antes I, Freund C, Helms V. Alternative binding modes of proline-rich peptides binding to the GYF domain. Biochemistry. 2005 May 3;44(17):6404-15. doi: 10.1021/bi0479914. PMID: 15850374.
18: Kofler M, Motzny K, Freund C. GYF domain proteomics reveals interaction sites in known and novel target proteins. Mol Cell Proteomics. 2005 Nov;4(11):1797-811. doi: 10.1074/mcp.M500129-MCP200. Epub 2005 Aug 23. PMID:16120600.
19: Kofler M, Heuer K, Zech T, Freund C. Recognition sequences for the GYF domain reveal a possible spliceosomal function of CD2BP2. J Biol Chem. 2004 Jul 2;279(27):28292-7. doi: 10.1074/jbc.M402008200. Epub 2004 Apr 22. PMID:15105431.
20: Heuer K, Kofler M, Langdon G, Thiemke K, Freund C. Structure of a helically extended SH3 domain of the T cell adapter protein ADAP. Structure. 2004 Apr;12(4):603-10. doi: 10.1016/j.str.2004.02.021. PMID: 15062083.
21: Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Kofler M, Jorissen RN, Nice EC, Burgess AW, Ward CW. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell. 2003 Feb;11(2):495-505. doi:10.1016/s1097-2765(03)00048-0. PMID: 12620236.
