Structural Basis for the Role of CHK as Tumor Suppressor Protein in Human Breast Cancer

摘要

To obtain structural information on aiK, an important anti-oncogene in breast cancer. Scope: A major clinical determinant of breast cancer is the presence in the cancer tumor cells of a protein called the Csk homologous kinase (CHK). CHK recognizes the tail of the breast cancer oncogene ErbB-2/neu receptor via its own SH2 domain and deactivates the bound Src kinases by phosphorylation. This deactivates the proliferative signaling pathways switched on by ErbB-2/neu. To determine how CHK flinctions at the molecular level, crystals of the cloned and purified, recombinant CHK SH2 domain will be obtained for x- ray diffraction studies from wlaich we can determine its precise, three-dimensional molecular structure. We will also use NMR spectroscopy should we not obtain adequate crystals. Major Findings: We obtained structural information from partial crystals of CHK and used NMR spectroscopy to identify binding interactions between CHK and the tail of the ErbB-2/neu receptor. Up-To-Date: By identifying the determinants in the SH2 domain of CHK, structural information is now available to help in the design of novel therapeutics forbreast cancer.