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Michael J. Eck, MD, PhD


Researcher


Researcher

  • Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

Contact Information

  • Office Phone Number(617) 632-5860
  • Fax(617) 632-4393

Bio

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:

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

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.

The structural basis of PTEN regulation by multi-site phosphorylation. Nat Struct Mol Biol. 2021 Oct; 28(10):858-868.
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Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation. Proc Natl Acad Sci U S A. 2021 Sep 07; 118(36).
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Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer. NPJ Precis Oncol. 2021 Jul 16; 5(1):66.
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A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer. Protein Sci. 2021 Aug; 30(8):1535-1553.
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The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors. Dev Neurosci. 2020; 42(5-6):170-186.
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Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations. Angew Chem Int Ed Engl. 2020 08 17; 59(34):14481-14489.
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The protein kinase Akt acts as a coat adaptor in endocytic recycling. Nat Cell Biol. 2020 08; 22(8):927-933.
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Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors. J Med Chem. 2020 04 23; 63(8):4293-4305.
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Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors. ACS Med Chem Lett. 2019 Nov 14; 10(11):1549-1553.
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Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. Nature. 2019 11; 575(7783):545-550.
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A driving test for oncogenic mutations. J Biol Chem. 2019 06 14; 294(24):9390-9391.
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Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor. Cancer Discov. 2019 07; 9(7):926-943.
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Discovery and Structural Characterization of ATP-Site Ligands for the Wild-Type and V617F Mutant JAK2 Pseudokinase Domain. ACS Chem Biol. 2019 04 19; 14(4):587-593.
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Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor. Angew Chem Int Ed Engl. 2018 09 03; 57(36):11629-11633.
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Micro-nano-bio acoustic system for the detection of foodborne pathogens in real samples. Biosens Bioelectron. 2018 Jul 15; 111:52-58.
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Correction: MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife. 2018 03 12; 7.
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MELK is not necessary for the proliferation of basal-like breast cancer cells. Elife. 2017 09 19; 6.
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Crystal Structure of Leiomodin 2 in Complex with Actin: A Structural and Functional Reexamination. Biophys J. 2017 Aug 22; 113(4):889-899.
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CRKL Mediates p110ß-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. Cell Rep. 2017 07 18; 20(3):549-557.
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Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors. Cancer Res. 2017 05 15; 77(10):2712-2721.
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Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression. Nat Commun. 2017 03 27; 8:14892.
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Leveraging Gas-Phase Fragmentation Pathways for Improved Identification and Selective Detection of Targets Modified by Covalent Probes. Anal Chem. 2016 12 20; 88(24):12248-12254.
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Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival. Proc Natl Acad Sci U S A. 2016 08 30; 113(35):9810-5.
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Crystal Structure of the FERM-SH2 Module of Human Jak2. PLoS One. 2016; 11(5):e0156218.
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Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016 06 02; 534(7605):129-32.
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Data publication with the structural biology data grid supports live analysis. Nat Commun. 2016 Mar 07; 7:10882.
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SPLINTS: small-molecule protein ligand interface stabilizers. Curr Opin Struct Biol. 2016 Apr; 37:115-22.
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EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src. Nat Struct Mol Biol. 2015 Dec; 22(12):983-90.
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Development of Selective Covalent Janus Kinase 3 Inhibitors. J Med Chem. 2015 Aug 27; 58(16):6589-606.
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Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6. Nat Struct Mol Biol. 2015 Sep; 22(9):703-711.
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Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia. 2016 Jan; 30(1):173-81.
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Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. Cancer Cell. 2015 Jul 13; 28(1):29-41.
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Structure of a Bud6/Actin Complex Reveals a Novel WH2-like Actin Monomer Recruitment Motif. Structure. 2015 Aug 04; 23(8):1492-1499.
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EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors. Clin Cancer Res. 2015 Sep 01; 21(17):3913-23.
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PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov. 2014 Dec; 4(12):1430-47.
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Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. Proc Natl Acad Sci U S A. 2014 Aug 05; 111(31):E3177-86.
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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 Jun 04; 13:141.
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MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife. 2014 May 20; 3:e01763.
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JAK-cytokine receptor recognition, unboxed. Nat Struct Mol Biol. 2014 May; 21(5):431-3.
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Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov. 2014 Apr; 4(4):452-65.
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Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med. 2013 Dec 18; 5(216):216ra177.
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Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res. 2013 Nov 15; 73(22):6770-9.
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Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proc Natl Acad Sci U S A. 2013 Sep 17; 110(38):E3595-604.
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Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat Struct Mol Biol. 2013 Oct; 20(10):1221-3.
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Structure-guided inhibitor design expands the scope of analog-sensitive kinase technology. ACS Chem Biol. 2013 Sep 20; 8(9):1931-8.
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Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep. 2013 Mar 28; 3(3):747-58.
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Structure of the formin-interaction domain of the actin nucleation-promoting factor Bud6. Proc Natl Acad Sci U S A. 2012 Dec 11; 109(50):E3424-33.
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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 Sep 04; 109(36):14476-81.
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Cyclic di-GMP sensing via the innate immune signaling protein STING. Mol Cell. 2012 Jun 29; 46(6):735-45.
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EGFR in limbo. Cell. 2012 May 11; 149(4):735-7.
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Functional characterization of an isoform-selective inhibitor of PI3K-p110ß as a potential anticancer agent. Cancer Discov. 2012 May; 2(5):425-33.
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Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med. 2012 Feb 13; 209(2):259-73.
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EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma. Clin Cancer Res. 2012 Mar 15; 18(6):1790-7.
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Tyrosine phosphorylation of Rac1: a role in regulation of cell spreading. PLoS One. 2011; 6(12):e28587.
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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.
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Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011 Jun; 1(1):78-89.
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Crystal structure of a coiled-coil domain from human ROCK I. PLoS One. 2011 Mar 21; 6(3):e18080.
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Binucleine 2, an isoform-specific inhibitor of Drosophila Aurora B kinase, provides insights into the mechanism of cytokinesis. ACS Chem Biol. 2010 Nov 19; 5(11):1015-20.
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The FERM domain: organizing the structure and function of FAK. Nat Rev Mol Cell Biol. 2010 Nov; 11(11):802-14.
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The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res. 2010 Dec 15; 70(24):10038-43.
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Crystal structure of a complex between amino and carboxy terminal fragments of mDia1: insights into autoinhibition of diaphanous-related formins. PLoS One. 2010 Sep 30; 5(9).
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Structural basis for the recognition of N-end rule substrates by the UBR box of ubiquitin ligases. Nat Struct Mol Biol. 2010 Oct; 17(10):1175-81.
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Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009 Dec 24; 462(7276):1070-4.
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Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta. 2010 Mar; 1804(3):559-66.
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[Palmar wrist arthroscopy for evaluation of concomitant carpal lesions in operative treatment of distal intraarticular radius fractures]. Handchir Mikrochir Plast Chir. 2009 Oct; 41(5):295-9.
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The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl. Curr Opin Cell Biol. 2009 Apr; 21(2):288-95.
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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(11):e3800.
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The Skap-hom dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch. Mol Cell. 2008 Nov 21; 32(4):564-75.
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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.
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Spatial and temporal regulation of focal adhesion kinase activity in living cells. Mol Cell Biol. 2008 Jan; 28(1):201-14.
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Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell. 2007 Jul; 12(1):81-93.
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Structural basis for the autoinhibition of focal adhesion kinase. Cell. 2007 Jun 15; 129(6):1177-87.
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Structure of the FH2 domain of Daam1: implications for formin regulation of actin assembly. J Mol Biol. 2007 Jun 22; 369(5):1258-69.
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Structure-guided development of affinity probes for tyrosine kinases using chemical genetics. Nat Chem Biol. 2007 Apr; 3(4):229-38.
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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.
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Mechanism and function of formins in the control of actin assembly. Annu Rev Biochem. 2007; 76:593-627.
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Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci U S A. 2006 May 16; 103(20):7817-22.
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Structure of the autoinhibitory switch in formin mDia1. Structure. 2006 Feb; 14(2):257-63.
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Crystal structure of the FERM domain of focal adhesion kinase. J Biol Chem. 2006 Jan 06; 281(1):252-9.
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Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Blood. 2005 Aug 01; 106(3):996-1002.
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Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005 Apr; 7(4):387-97.
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EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005 Feb 24; 352(8):786-92.
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A case of metastasizing invasive hydatidiform mole. Is less--less good? Review of the literature with regard to adequate treatment. Eur J Gynaecol Oncol. 2005; 26(2):158-62.
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Structure and regulation of Src family kinases. Oncogene. 2004 Oct 18; 23(48):7918-27.
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Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell. 2004 Jul; 6(1):33-43.
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Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML. Blood. 2004 Sep 15; 104(6):1855-8.
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FERM domain interaction promotes FAK signaling. Mol Cell Biol. 2004 Jun; 24(12):5353-68.
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EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004 Jun 04; 304(5676):1497-500.
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SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9. Int Immunol. 2004 May; 16(5):727-36.
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Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture. Cell. 2004 Mar 05; 116(5):711-23.
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A conserved mechanism for Bni1- and mDia1-induced actin assembly and dual regulation of Bni1 by Bud6 and profilin. Mol Biol Cell. 2004 Feb; 15(2):896-907.
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Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. J Biol Chem. 2003 Dec 26; 278(52):52964-71.
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The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nat Rev Immunol. 2003 Oct; 3(10):813-21.
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A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science. 2003 Sep 19; 301(5640):1725-8.
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Structural basis of degradation signal recognition by SspB, a specificity-enhancing factor for the ClpXP proteolytic machine. Mol Cell. 2003 Jul; 12(1):75-86.
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Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Nat Struct Biol. 2003 Jul; 10(7):504-12.
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Assembling atomic resolution views of the immunological synapse. Curr Opin Immunol. 2003 Jun; 15(3):286-93.
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Origins of peptide selectivity and phosphoinositide binding revealed by structures of disabled-1 PTB domain complexes. Structure. 2003 May; 11(5):569-79.
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SAP couples Fyn to SLAM immune receptors. Nat Cell Biol. 2003 Feb; 5(2):155-60.
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Homotetrameric structure of the SNAP-23 N-terminal coiled-coil domain. J Biol Chem. 2003 Apr 11; 278(15):13462-7.
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Specificity in signaling by c-Yes. Front Biosci. 2003 Jan 01; 8:s185-205.
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Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha. Proc Natl Acad Sci U S A. 2002 Apr 16; 99(8):5367-72.
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Mutant tyrosine kinases with unnatural nucleotide specificity retain the structure and phospho-acceptor specificity of the wild-type enzyme. Chem Biol. 2002 Jan; 9(1):25-33.
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Structure of a human Tcf4-beta-catenin complex. Nat Struct Biol. 2001 Dec; 8(12):1053-7.
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Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. EMBO J. 2001 Nov 01; 20(21):5840-52.
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Mapping of epitopes in discoidin domain receptor 1 critical for collagen binding. J Biol Chem. 2001 Dec 07; 276(49):45952-8.
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Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients. J Biol Chem. 2001 Sep 28; 276(39):36809-16.
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Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. Nat Struct Biol. 2001 Jun; 8(6):499-504.
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Structure of the cooperative allosteric anthranilate synthase from Salmonella typhimurium. Nat Struct Biol. 2001 Mar; 8(3):243-7.
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Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell. 2000 Aug 04; 102(3):387-97.
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Structure of a WW domain containing fragment of dystrophin in complex with beta-dystroglycan. Nat Struct Biol. 2000 Aug; 7(8):634-8.
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Adapting to multiple personalities: Cbl is also a RING finger ubiquitin ligase. Biochim Biophys Acta. 2000 Jul 31; 1471(1):M1-M12.
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Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Mol Cell. 1999 Oct; 4(4):555-61.
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The Cbl protooncoprotein: a negative regulator of immune receptor signal transduction. Immunol Today. 1999 Aug; 20(8):375-82.
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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 Jul 20; 96(15):8378-83.
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Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol Cell. 1999 May; 3(5):629-38.
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Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature. 1999 Mar 04; 398(6722):84-90.
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Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression. Biochem J. 1998 Nov 01; 335 ( Pt 3):557-65.
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A Zn2+ ion links the cytoplasmic tail of CD4 and the N-terminal region of Lck. J Biol Chem. 1998 Jul 24; 273(30):18729-33.
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Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20; 92(4):441-50.
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Peptide and protein phosphorylation by protein tyrosine kinase Csk: insights into specificity and mechanism. Biochemistry. 1998 Jan 06; 37(1):165-72.
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Impaired secretion of very low density lipoprotein-triglycerides by apolipoprotein E- deficient mouse hepatocytes. J Clin Invest. 1997 Dec 01; 100(11):2915-22.
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Three-dimensional structure of the tyrosine kinase c-Src. Nature. 1997 Feb 13; 385(6617):595-602.
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Analysis of the physical properties and molecular modeling of Sec13: A WD repeat protein involved in vesicular traffic. Biochemistry. 1996 Dec 03; 35(48):15215-21.
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Phosphorylated T cell receptor zeta-chain and ZAP70 tandem SH2 domains form a 1:3 complex in vitro. Eur J Biochem. 1996 Jun 01; 238(2):440-5.
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Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Cell. 1996 May 31; 85(5):695-705.
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Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes. Nat Struct Biol. 1996 Apr; 3(4):364-74.
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Spatial constraints on the recognition of phosphoproteins by the tandem SH2 domains of the phosphatase SH-PTP2. Nature. 1996 Jan 18; 379(6562):277-80.
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A new flavor in phosphotyrosine recognition. Structure. 1995 May 15; 3(5):421-4.
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SH3 domains. Minding your p's and q's. Curr Biol. 1995 Apr 01; 5(4):364-7.
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Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature. 1995 Feb 09; 373(6514):536-9.
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Two crystal forms of the extracellular domain of type I tumor necrosis factor receptor. J Mol Biol. 1994 Jun 03; 239(2):332-5.
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Role of acidic amino acids in the allosteric modulation by gallamine of antagonist binding at the m2 muscarinic acetylcholine receptor. Mol Pharmacol. 1994 May; 45(5):983-90.
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Structure of the regulatory domains of the Src-family tyrosine kinase Lck. Nature. 1994 Apr 21; 368(6473):764-9.
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Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck. Nature. 1993 Mar 04; 362(6415):87-91.
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The structure of human lymphotoxin (tumor necrosis factor-beta) at 1.9-A resolution. J Biol Chem. 1992 Feb 05; 267(4):2119-22.
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The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding. J Biol Chem. 1989 Oct 15; 264(29):17595-605.
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