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.

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