• Researcher Profile

    Michael J. Eck, MD, PhD

     
    Michael J. Eck, MD, PhD
     
    Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

    Office phone: 617-632-5860
    Fax: 617-632-4393
    Email: michael_eck@dfci.harvard.edu
    Website: The Eck Laboratory

    Preferred contact method: office phone
     
     

    Research Department

    Cancer Biology

    Area of Research

    Structural Biology of Cell Signaling and Cancer


    Dana-Farber Cancer Institute
    450 Brookline Avenue
    Smith 1036
    Boston, MA 02215

    Biography

    Dr. Eck received his M.D. and Ph.D. from the University of Texas Southwestern Medical School in 1991. He trained as a postdoctoral fellow with Dr. Stephen Harrison at Children’s Hospital and Harvard Medical School before joining the DFCI in 1996. Dr. Eck is currently Professor of Biological Chemistry and Molecular Pharmacology at the Dana-Farber Cancer Institute and Harvard Medical School. His research focuses on the structure and regulation of tyrosine kinases in cancer and on structure-based approaches to discovery of novel inhibitors. The Eck lab also studies the structure of formin proteins and their role in assembling the actin cytoskeleton.

    Recent Awards

    • AACR Team Science Award (DF/HCC Thoracic Oncology Research Team), 2010
    • World Class Scholar, Korean Ministry of Science and Technology, Korea University, 2009
    • Scholar Award, Leukemia and Lymphoma Society of America, 2002
    • Career Award in the Biomedical Sciences, Burroughs Wellcome Fund, 1997

    Research

    Structural Biology of Cell Signaling and Cancer

    We use biochemical and structural methods (primarily X-ray crystallography) to study the structure and regulation of tyrosine kinases that are important in cancer. We are especially interested in understanding how cancer-causing mutations lead to loss of normal kinase regulation, and in using structural approaches to develop new anticancer drugs. Active areas of investigation include: (1) the structure and regulation of Jak-family kinases and their interactions with cytokine receptors, (2) lung cancer-derived mutations in the epidermal growth factor receptor (EGFR), (3) the structural biology of focal adhesion kinase (FAK), and (4) formin proteins and their role in assembling the actin cytoskeleton.

    Jak family kinases are central mediators of cytokine signaling, and mutations and chromosomal translocations of Jaks lead to hematopoietic cancers.  In particular, the V617F mutation in Jak2 causes myeloproliferative neoplasms.  We have recently discovered how this mutation alters the conformation of a regulatory “pseudokinase” domain that is unique to Jak-family members, and we are working to understand how this signal is in turn transmitted to the kinase domain.  A long-term goal is to discover inhibitors that specifically inhibit this mutant, without interfering with the function of other Jaks in normal cells.  We are also working to understand how the erythropoietin receptor binds and regulates Jak2.

    Mutations in the EGFR tyrosine kinase are a common cause of non-small cell lung cancer. Our structural and biochemical studies have shown how several of these mutations activate the kinase and simultaneously alter its sensitivity to inhibitors such as the drug erlotinib.  We have extensively characterized the drug-resistant EGFR T790M mutant and with our collaborators at the Dana-Farber, we developed a novel inhibitor WZ4002 that is highly active against this mutant.

    Because FAK signaling is critical for cell migration, it is thought to play an important role in the invasiveness and metastasis of human tumors. We determined the structure of FAK, which shows how its catalytic activity is regulated by its N-terminal “FERM” region.  We are currently studying how this inhibitory interaction of the FERM domain is released to activate FAK.  Additionally, to facilitate development of drugs specifically targeting FAK, we have analyzed the structure of FAK in complex with a number of inhibitors.

    Finally, in addition to tyrosine kinases, the laboratory studies formins, a large family of proteins that direct the assembly of the actin cytoskeleton in response to activation by Rho family GTPases. We discovered the unique “tethered-dimer” architecture of the formin FH2 domain, which is especially adapted for its role in directly assembling linear actin filaments.  Additionally we are studying formin regulation and interactions with accessory proteins that allow formins to build distinct actin structures for particular cellular processes.

    Select Publications

    • Kim PW, Sun ZY, Blacklow SC, Wagner G, Eck MJ. A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science. 2003 Sep 19; 301(5640):1725-8.
    • Xu Y, Moseley JB, Sagot I, Poy F, Pellman D, Goode BL, Eck MJ. Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture. Cell. 2004 Mar 5; 116(5):711-23.
    • Boggon TJ, Li Y, Manley PW, Eck MJ. Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Blood. 2005 Aug 1; 106(3):996-1002. PMCID: PMC1895152
    • Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. 2007 Mar; 11(3):217-27. PMCID: PMC1939942
    • Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ. Structural basis for the autoinhibition of focal adhesion kinase. Cell. 2007 Jun 15; 129(6):1177-87. PMCID: PMC2077847
    • Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008 Feb 12; 105(6):2070-5. PMCID: PMC2538882
    • Swanson KD, Tang Y, Ceccarelli DF, Poy F, Sliwa JP, Neel BG, Eck MJ. The Skap-hom dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch. Mol Cell. 2008 Nov 21; 32(4):564-75. PMCID: PMC2628593
    • Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ, Gray NS, Jänne PA. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009 Dec 24; 462(7276):1070-4. PMCID: PMC2879581
    • Vizcarra CL, Kreutz B, Rodal AA, Toms AV, Lu J, Zheng W, Quinlan ME, Eck MJ. Structure and function of the interacting domains of Spire and Fmn-family formins. Proc Natl Acad Sci U S A. 2011 Jul 19; 108(29):11884-9. PMCID: PMC3141961
    • Tu D, Graziano BR, Park E, Zheng W, Li Y, Goode BL, Eck MJ.  Proc Natl Acad Sci USA.   Structure of the formin-interaction domain of the actin nucleation-promoting factor Bud6. 2012 Dec 11:109(50):E3424-33.  doi:  10.1073/pnas.  1203035109.  Epub 2012 Nov 16.  PMID:  23161908
    • Tu D, Zhu Z, Zhou AY, Yun CH, Lee KE, Toms AV, Li Y, Dunn GP, Chan E, Thai T, Yang S, Ficarro SB, Marto JA, Jeon H, Hahn WC, Barbie DA, Eck MJ. Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep. 2013 Mar 28;3(3):747-58. doi:  10.1016/j.celrep.2013.01.033. Epub 2013 Feb 28. PubMed PMID: 23453972. In process at NIHMS. NIHMS ID: NIHMS486692

    Investigators

    • Jeon, Hyesung, PhD

    Trainees

    • Eves, Taylor, PhD
    • Li, Qing, PhD
    • McNally, Randall, PhD
    • Park, Eunyoung, PhD
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