Abstract

The epidermal growth factor receptor (EGFR) homolog Her-2 forms heterodimers with other EGFR family members in response to several EGF-like ligands. These dimers result in activation of the cytoplasmic kinase domain of Her-2, which typically leads to cell proliferation. Her-2 expression is frequently elevated in cancers including those of the breast, ovaries, and lung. Activation of the Her-2 kinase through inappropriate dimerization is thought to contribute to the development and severity of these malignancies. Therapies that reverse Her-2 activation are thus of great interest, and antibodies against the extracellular domain of Her-2, trade named Herceptin, have recently proven an effective treatment in the subset of breast cancers in which Her-2 is overexpressed. These Her-2 overexpressing cancers account for about 50,000 of the 175,000 new cases of breast cancer diagnosed each year in the United States. No atomic structure exists for the extracellular domain of any EGFR family member. We have grown diffraction-quality crystals of homodimers of the 629 amino acid extracellular domain (ECD) of Her-2.
Our first aim i s to complete the crystal structure of the Her-2 ECD to characterize the Her-2 dimer interface as well as provide a molecular basis for interpreting the function of EGFR family members. Peptides derived from Her-2 sequences found at the dimer interface will be tested for their ability to block Her-2 dimerization and thus potentially serve as lead compounds for the development of new anti-cancer drugs.
Our second aim i s to determine the structures of the ECDs of Her-1 and Her-3 in the absence of bound ligand to provide a basis for comparison among different EGFRs as well as with Her ECD structures determined with bound ligand.
Our third aim i s to determine the structure of an active signaling complex of the Her-2 and Her-3 ECDs with the receptor-binding domain of Neu Differentiation Factor (NDF; heregulin).
Our final aim i s to determine the structure of a complex of the Her-1 ECD with EGF. These studies will lead to investigation of new target-based therapies for human cancers and reveal the atomic details of ligand specificity and signal transduction in the EGFR family.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090466-03
Application #
6718474
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Ault, Grace S
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$232,988
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Ward, Matthew D; Leahy, Daniel J (2015) Kinase activator-receiver preference in ErbB heterodimers is determined by intracellular regions and is not coupled to extracellular asymmetry. J Biol Chem 290:1570-9
Wang, Yun; Kavran, Jennifer M; Chen, Zan et al. (2014) Regulation of S-adenosylhomocysteine hydrolase by lysine acetylation. J Biol Chem 289:31361-72
Han, Jeehae; Ryu, Seungjin; Moskowitz, David M et al. (2013) Discovery of novel non-synonymous SNP variants in 988 candidate genes from 6 centenarians by target capture and next-generation sequencing. Mech Ageing Dev 134:478-85
Hollmen, Maija; Liu, Ping; Kurppa, Kari et al. (2012) Proteolytic processing of ErbB4 in breast cancer. PLoS One 7:e39413
Merte, Janna; Wang, Qiang; Vander Kooi, Craig W et al. (2010) A forward genetic screen in mice identifies Sema3A(K108N), which binds to neuropilin-1 but cannot signal. J Neurosci 30:5767-75
Qiu, Chen; Tarrant, Mary K; Boronina, Tatiana et al. (2009) In vitro enzymatic characterization of near full length EGFR in activated and inhibited states. Biochemistry 48:6624-32
Qiu, Chen; Tarrant, Mary K; Choi, Sung Hee et al. (2008) Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure 16:460-7
Qiu, Chen; Lienhard, Susanne; Hynes, Nancy E et al. (2008) Memo is homologous to nonheme iron dioxygenases and binds an ErbB2-derived phosphopeptide in its vestigial active site. J Biol Chem 283:2734-40
Zhang, Fuming; McLellan, Jason S; Ayala, Alondra M et al. (2007) Kinetic and structural studies on interactions between heparin or heparan sulfate and proteins of the hedgehog signaling pathway. Biochemistry 46:3933-41
Vander Kooi, Craig W; Jusino, Manuel A; Perman, Benjamin et al. (2007) Structural basis for ligand and heparin binding to neuropilin B domains. Proc Natl Acad Sci U S A 104:6152-7

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