Research Department

Cancer Biology

Area of Research

Biography

Dr. Eck received his MD and PhD from the University of Texas Southwestern Medical School in 1991. He trained as a postdoctoral fellow at Children’s Hospital and Harvard Medical School, where he determined the three-dimensional structure of the Src tyrosine kinase. In 1997, he joined DFCI, where his laboratory studies the structure of proteins that control cell growth and division.

Recent Awards

• Scholar Award, Leukemia and Lymphoma Society of America, 2002
• Career Award in the Biomedical Sciences, Burroughs Wellcome Fund, 1997

Research

Our laboratory seeks to define molecular interactions that regulate intracellular signaling and rearrangement of the actin cytoskeleton. We use biochemical and structural methods (primarily X-ray crystallography) to understand how complex multidomain proteins are inhibited and activated by their networks of interactions within the cell. We are especially interested in determining the structure of aberrant signaling proteins and complexes that underlie cancer, and in facilitating development of anticancer drugs. Active areas of investigation include: (1) the structural biology of focal adhesion kinase (FAK) and its interactions with integrins and Src-family kinases, (2) regulation of Src-family kinases in antigen-dependent T cell activation, (3) the structure and regulation of JAK-family kinases and their interactions with cytokine receptors, (4) mechanisms of activation and inhibition of lung cancer-derived mutations in the epidermal growth factor receptor (EGF-R), and (5) the structure and regulation of diaphanous-related formin proteins.
Since FAK signaling is critical for changes in cell morphology and migration, it may be an important factor in the invasiveness and metastasis of human tumors. FAK catalytic activity is regulated by its N-terminal region, which contains a FERM domain - also thought to associate with the cytoplasmic portion of a subset of integrin receptors. To understand FAK regulation, we are working to determine the structure of FAK in its autoinhibited conformation and in complex with relevant binding partners.
We are also studying a number of proteins that control T cell activation, including Src-family kinases Lck and Fyn. We have recently determined structures of the N-terminal domain of Lck in complex with the cytoplasmic tails of T cell coreceptors CD4 and CD8 - work that has important implications for understanding CD4 internalization.
JAK family kinases are central mediators of cytokine signaling. Because mutations and chromosomal translocations of JAK family members underlie diverse lymphoproliferative and hematoproliferative disorders, these kinases are attractive targets for anticancer and immunosuppressive drugs. We determined the structure of the kinase domain of JAK3, and are working to determine the structure of intact JAK2 to understand its regulation and association with the erythropoietin receptor.
Mutations in the EGF-R tyrosine kinase domain have recently been discovered in a subset of lung cancers. We are determining structures of the EGF-R kinase bearing these mutations to understand the mechanisms by which these mutations activate the kinase and to allow rational design of more potent and specific inhibitors.
The diaphanous-related formins are proteins that direct the nucleation and assembly of actin filaments in response to activation by Rho family GTPases. We are elucidating the structure of the actin-nucleating FH2 domain of mDia1 and its assembly into an oligomeric complex with N-terminal portions of the protein in the autoinhibited state.

Select Publications

• 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.
• 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.
• Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
• Moseley JB, Sagot I, Manning AL, Xu Y, Eck MJ, Pellman D, Goode BL. A conserved mechanism for Bni1- and mDia1-induced actin assembly and dual regulation of Bni1 by Bud6 and profilin. Mol Biol Cell 2004;15:896-907.
• Boggon TJ, Eck MJ. Structure and regulation of Src family kinases. Oncogene 2004;23:7918-27.
• Song HK, Eck MJ. Structural basis of degradation signal recognition by SspB, a specificity-enhancing factor for the ClpXP proteolytic machine. Mol Cell 2003;12:75-86.
• 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.
• 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.
• Freedman SJ, Song HK, Xu Y, Sun ZY, Eck MJ. Homotetrameric structure of the SNAP-23 N-terminal coiled-coil domain. J Biol Chem 2003;278:13462-7.
• 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.

Trainees

• McNally, Randall, PhD
• Tu, Daqi, PhD
• Zheng, Wei, PhD
• Park, Eunyoung, PhD
• Yun, Caihong, PhD
• Toms, Angela, PhD
• Kreutz, Barry, PhD