Photo of Michael J. Eck,  MD, PhD

Michael J. Eck, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-5860
Fax: (617) 632-4393


eck@red.dfci.harvard.edu

Michael J. Eck, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School
  • Professor, Cancer Biology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

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.

Publications

Powered by Harvard Catalyst
  • Cho J, Bass AJ, Lawrence MS, Cibulskis K, Cho A, Lee SN, Yamauchi M, Wagle N, Pochanard P, Kim N, Park AK, Won J, Hur HS, Greulich H, Ogino S, Sougnez C, Voet D, Tabernero J, Jimenez J, Baselga J, Gabriel SB, Lander ES, Getz G, Eck MJ, Park WY, Meyerson M. Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab. Mol Cancer 2014; 13:141. PubMed
  • McNally R, Eck MJ. JAK-cytokine receptor recognition, unboxed. Nat Struct Mol Biol 2014; 21:431-3. PubMed
  • Zhu Z, Aref AR, Cohoon TJ, Barbie TU, Imamura Y, Yang S, Moody SE, Shen RR, Schinzel AC, Thai TC, Reibel JB, Tamayo P, Godfrey JT, Qian ZR, Page AN, Maciag K, Chan EM, Silkworth W, Labowsky MT, Rozhansky L, Mesirov JP, Gillanders WE, Ogino S, Hacohen N, Gaudet S, Eck MJ, Engelman JA, Corcoran RB, Wong KK, Hahn WC, Barbie DA. Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. 2014; 4:452-65. PubMed
  • Wang Y, Lee YM, Baitsch L, Huang A, Xiang Y, Tong H, Lako A, Von T, Choi C, Lim E, Min J, Li L, Stegmeier F, Schlegel R, Eck MJ, Gray NS, Mitchison TJ, Zhao JJ. MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife 2014. PubMed
  • Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, Huberman MS, Cohen DW, Nakayama S, Ishioka K, Yamaguchi N, Hanna M, Oxnard GR, Lathan CS, Moran T, Sequist LV, Chaft JE, Riely GJ, Arcila ME, Soo RA, Meyerson M, Eck MJ, Kobayashi SS, Costa DB. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013; 5:216ra177. PubMed
  • Cho J, Chen L, Sangji N, Okabe T, Yonesaka K, Francis JM, Flavin RJ, Johnson W, Kwon J, Yu S, Greulich H, Johnson BE, Eck MJ, Jänne PA, Wong KK, Meyerson M. Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res 2013; 73:6770-9. PubMed
  • Toms AV, Deshpande A, McNally R, Jeong Y, Rogers JM, Kim CU, Gruner SM, Ficarro SB, Marto JA, Sattler M, Griffin JD, Eck MJ. Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat Struct Mol Biol 2013; 20:1221-3. PubMed
  • Zhang C, Lopez MS, Dar AC, Ladow E, Finkbeiner S, Yun CH, Eck MJ, Shokat KM. Structure-guided inhibitor design expands the scope of analog-sensitive kinase technology. ACS Chem Biol 2013; 8:1931-8. PubMed
  • Red Brewer M, Yun CH, Lai D, Lemmon MA, Eck MJ, Pao W. Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proc Natl Acad Sci U S A 2013; 110:E3595-604. PubMed
  • 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; 3:747-58. PubMed
  • Tu D, Graziano BR, Park E, Zheng W, Li Y, Goode BL, Eck MJ. Structure of the formin-interaction domain of the actin nucleation-promoting factor Bud6. Proc Natl Acad Sci U S A 2012. PubMed
  • Greulich H, Kaplan B, Mertins P, Chen TH, Tanaka KE, Yun CH, Zhang X, Lee SH, Cho J, Ambrogio L, Liao R, Imielinski M, Banerji S, Berger AH, Lawrence MS, Zhang J, Pho NH, Walker SR, Winckler W, Getz G, Frank D, Hahn WC, Eck MJ, Mani DR, Jaffe JD, Carr SA, Wong KK, Meyerson M. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A 2012; 109:14476-81. PubMed
  • Yin Q, Tian Y, Kabaleeswaran V, Jiang X, Tu D, Eck MJ, Chen ZJ, Wu H. Cyclic di-GMP sensing via the innate immune signaling protein STING. Mol Cell 2012; 46:735-45. PubMed
  • Tu D, Li Y, Song HK, Toms AV, Gould CJ, Ficarro SB, Marto JA, Goode BL, Eck MJ. Crystal Structure of a Coiled-Coil Domain from Human ROCK I. PLoS ONE 2011; 6:e18080. PubMed
  • Sasaki T, Okuda K, Zheng W, Butrynski J, Capelletti M, Wang L, Gray NS, Wilner K, Christensen JG, Demetri G, Shapiro GI, Rodig SJ, Eck MJ, Jänne PA. The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010; 70:10038-43. PubMed
  • Frame MC, Patel H, Serrels B, Lietha D, Eck MJ. The FERM domain: organizing the structure and function of FAK. Nat Rev Mol Cell Biol 2010; 11:802-14. PubMed
  • Choi WS, Jeong BC, Joo YJ, Lee MR, Kim J, Eck MJ, Song HK. Structural basis for the recognition of N-end rule substrates by the UBR box of ubiquitin ligases. Nat Struct Mol Biol 2010; 17:1175-81. PubMed
  • Smurnyy Y, Toms AV, Hickson GR, Eck MJ, Eggert US. Binucleine 2, an Isoform-Specific Inhibitor of Drosophila Aurora B Kinase, Provides Insights into the Mechanism of Cytokinesis. ACS Chem Biol 2010. PubMed
  • Eck MJ, Yun CH. Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta 2010; 1804:559-66. PubMed
  • Nezami A, Poy F, Toms A, Zheng W, Eck MJ. Crystal structure of a complex between amino and carboxy terminal fragments of mDia1: insights into autoinhibition of diaphanous-related formins. PLoS ONE 2010. PubMed
  • 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; 462:1070-4. PubMed
  • Eck MJ,Manley PW. The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl. Curr Opin Cell Biol 2009; 21:288-95. PubMed
  • 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; 32:564-75. PubMed
  • 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; 105:2070-5. PubMed
  • Cai X, Lietha D, Ceccarelli DF, Karginov AV, Rajfur Z, Jacobson K, Hahn KM, Eck MJ, Schaller MD. Spatial and temporal regulation of focal adhesion kinase activity in living cells. Mol Cell Biol 2007; 28:201-14. PubMed
  • Lietha D,Eck MJ. Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation. PLoS ONE 2008; 3:e3800. PubMed
  • Li D, Shimamura T, Ji H, Chen L, Haringsma HJ, McNamara K, Liang MC, Perera SA, Zaghlul S, Borgman CL, Kubo S, Takahashi M, Sun Y, Chirieac LR, Padera RF, Lindeman NI, J. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 2007; 12:81-93. PubMed
  • Lu J, Meng W, Poy F, Maiti S, Goode BL, Eck MJ. Structure of the FH2 domain of Daam1: implications for formin regulation of actin assembly. J Mol Biol 2007; 369:1258-69. PubMed
  • Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ. Structural basis for the autoinhibition of focal adhesion kinase. Cell 2007; 129:1177-87. PubMed
  • 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; 11:217-27. PubMed
  • Goode BL, Eck MJ. Mechanism and function of formins in the control of actin assembly. Annu Rev Biochem 2007; 76:593-627. PubMed
  • Ji H, Zhao X, Yuza Y, Shimamura T, Li D, Protopopov A, Jung BL, McNamara K, Xia H, Glatt KA, Thomas RK, Sasaki H, Horner JW, Eck M, Mitchell A, Sun Y, Al-Hashem R, Bronson RT, Rabindran SK, Discafani CM, Maher E, Shapiro GI, Meyerson M, Wong KK. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci U S A 2006; 103:7817-22. PubMed
  • Nezami AG, Poy F, Eck MJ. Structure of the autoinhibitory switch in formin mDia1. Structure 2006; 14:257-63. PubMed
  • Ceccarelli DF, Song HK, Poy F, Schaller MD, Eck MJ. Crystal structure of the FERM domain of focal adhesion kinase. J Biol Chem 2005; 281:252-9. PubMed
  • Honig A, Rieger L, Thanner F, Eck M, Sutterlin M, Dietl J. Placenta percreta with subsequent uterine rupture at 15 weeks of gestation after two previous cesarean sections. J Obstet Gynaecol Res 2005; 31:439-43. PubMed
  • Adam P, Zettl A, Zollner U, Dietl J, M. Metastasizing vulvar carcinosarcoma with squamous carcinomatous and leiomyosarcomatous differentiation: genetic evidence of clonal origin. Hum Pathol 2005; 36:1143-7. PubMed
  • Boggon TJ, Li Y, Manley PW, Eck MJ. Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Blood 2005; 106:996-1002. PubMed
  • Schmausser B, Andrulis M, Endrich S, M. Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori. Int J Med Microbiol 2005; 295:179-85. PubMed
  • Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7:387-97. PubMed
  • Kobayashi S, Boggon TJ, Dayaram T, J. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005; 352:786-92. PubMed
  • Schmausser B, Endrich S, Br. The chemokine receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, Helicobacter pylori gastritis, gastric carcinoma and its precursor lesions and up-regulated by H. pylori. Clin Exp Immunol 2005; 139:323-7. PubMed
  • Boggon TJ, Eck MJ. Structure and regulation of Src family kinases. Oncogene 2004; 23:7918-27. PubMed
  • Jiang J, Paez JG, Lee JC, Bo R, Stone RM, DeAngelo DJ, Galinsky I, Wolpin BM, Jonasova A, Herman P, Fox EA, Boggon TJ, Eck MJ, Weisberg E, Griffin JD, Gilliland DG, Meyerson M, Sellers WR. Identification and Characterization of a Novel Activating Mutation of the FLT3 Tyrosine Kinase in AML. Blood 2004; 104:1855-8. PubMed
  • Kung AL, Zabludoff SD, France DS, Freedman SJ, Tanner EA, Vieira A, Cornell-Kennon S, Lee J, Wang B, Wang J, Memmert K, Naegeli HU, Petersen F, Eck MJ, Bair KW, Wood AW, Livingston DM. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 2004; 6:33-43. PubMed
  • Paez JG, J. EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science 2004; 304:1497-500. PubMed
  • 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; 116:711-23. PubMed
  • 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; 301:1725-8. PubMed
  • Freedman SJ, Sun ZY, Kung AL, France DS, Wagner G, Eck MJ. Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Nat Struct Biol 2003; 10:504-12. PubMed
  • Chan B, Lanyi A, Song HK, Griesbach J, Simarro-Grande M, Poy F, Howie D, Sumegi J, Terhorst C, Eck MJ. SAP couples Fyn to SLAM immune receptors. Nat Cell Biol 2003; 5:155-60. PubMed
  • Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, Eck MJ. Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha. Proc Natl Acad Sci U S A 2002; 99:5367-72. PubMed
  • Poy F, Lepourcelet M, Shivdasani RA, Eck MJ. Structure of a human Tcf4-beta-catenin complex. Nat Struct Biol 2001; 8:1053-7. PubMed
  • Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC. Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. Nat Struct Biol 2001; 8:499-504. PubMed
  • Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, Harrison SC. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell 2000; 102:387-97. PubMed
  • Poy F, Yaffe MB, Sayos J, Saxena K, Morra M, Sumegi J, Cantley LC, Terhorst C, Eck MJ. Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Mol Cell 1999; 4:555-61. PubMed
  • Dhe-Paganon S, Ottinger EA, Nolte RT, Eck MJ, Shoelson SE. Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH-PTB) targeting region of insulin receptor substrate 1. Proc Natl Acad Sci U S A 1999; 96:8378-83. PubMed
  • Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ. Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature 1999; 398:84-90. PubMed
  • Huse M, Eck MJ, Harrison SC. A Zn2+ ion links the cytoplasmic tail of CD4 and the N-terminal region of Lck. J Biol Chem 1998; 273:18729-33. PubMed
  • Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell 1998; 92:441-50. PubMed
  • Sondhi D, Xu W, Songyang Z, Eck MJ, Cole PA. Peptide and protein phosphorylation by protein tyrosine kinase Csk: insights into specificity and mechanism. Biochemistry 1998; 37:165-72. PubMed
  • Xu W, Harrison SC, Eck MJ. Three-dimensional structure of the tyrosine kinase c-Src. Nature 1997; 385:595-602. PubMed
  • Eck MJ, Dhe-Paganon S, Tr. Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Cell 1996; 85:695-705. PubMed
  • Nolte RT, Eck MJ, Schlessinger J, Shoelson SE, Harrison SC. Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes. Nat Struct Biol 1996; 3:364-74. PubMed
  • Eck MJ, Pluskey S, Tr. Spatial constraints on the recognition of phosphoproteins by the tandem SH2 domains of the phosphatase SH-PTP2. Nature 1996; 379:277-80. PubMed
  • Mayer BJ, Eck MJ. SH3 domains. Minding your p's and q's. Curr Biol 1995; 5:364-7. PubMed
  • Songyang Z, Carraway KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C. Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature 1995; 373:536-9. PubMed
  • Rodseth LE, Brandhuber B, Devine TQ, Eck MJ, Hale K, Naismith JH, Sprang SR. Two crystal forms of the extracellular domain of type I tumor necrosis factor receptor. J Mol Biol 1994; 239:332-5. PubMed
  • Eck MJ, Atwell SK, Shoelson SE, Harrison SC. Structure of the regulatory domains of the Src-family tyrosine kinase Lck. Nature 1994; 368:764-9. PubMed
  • Eck MJ, Shoelson SE, Harrison SC. Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck. Nature 1993; 362:87-91. PubMed
  • Eck MJ, Ultsch M, Rinderknecht E, de Vos AM, Sprang SR. The structure of human lymphotoxin (tumor necrosis factor-beta) at 1.9-A resolution. J Biol Chem 1992; 267:2119-22. PubMed
Hide